Use of botulinum toxin a for the treatment of blepharospasm and hemifacial spasm

Abstract

This invention relates to a modified botulinum neurotoxin A (BoNT / A) for the treatment of facial dystonia, including blepharospasm and hemifacial spasm, wherein the unit dose of the modified BoNT / A is greater than 240 pg (or greater than 8000 pg), wherein the modified BoNT / A is administered intramuscularly to the affected muscles of an individual, wherein the total dose administered during treatment is greater than 24,000 pg (or greater than 82,500 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and wherein the modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

Description

Technical Field

[0001] This invention relates to the treatment of disorders affecting the muscles of an individual's eyelids. Background Technology

[0002] Disorders affecting the eyelid muscles can negatively impact a patient's life. Among these disorders, blepharospasm and facial spasms (e.g., hemifacial spasm) are particularly unpleasant.

[0003] The primary characteristic of blepharospasm is the abnormal contraction of the orbicularis oculi muscle. More specifically, blepharospasm can manifest as uncontrollable excessive blinking and spasms in one or both eyes, further characterized by uncontrollable eyelid closure lasting longer than the typical blink reflex. Blepharospasm symptoms may recur and can last for hours or days at a time, and in some cases, the symptoms (such as twitching) can be chronic and persistent, posing a lifelong challenge to the individual with the condition. Other symptoms may include twitching that may radiate to the nose, face, and neck, dry eyes, and sensitivity to sunlight and bright light.

[0004] The cause of blepharospasm is unclear. It has been suggested that certain medications (such as those used to treat Parkinson's disease, estrogen replacement therapy, or acute benzodiazepine withdrawal) can induce blepharospasm. Blepharospasm can also be associated with brain disorders (including neurodegenerative diseases, basal ganglia dysfunction, and multiple sclerosis), brain injury, or head injury (such as concussion).

[0005] Hemifacial spasm is a motor disorder characterized by involuntary tonic-clonic contractions of mimicking muscles on one side of the face. While bilateral cases can occur, this is extremely rare. The affected muscles are those innervated by the facial nerve (cranial nerve VII). The initial symptoms of this disorder are usually located in the orbicularis oculi muscle and can spread to other facial expression muscles. Hemifacial spasm (HFS) has two forms: typical HFS and atypical HFS. In the typical form, the twitching / spasm usually begins in the orbicularis oculi muscle of the lower eyelid. Over time, it spreads to the entire eyelid and then to the orbicularis oris around the lips and the buccinator muscles in the zygomatic region. In atypical HFS, the twitching / spasm usually begins in the orbicularis oris around the lips and the buccinator muscles in the lower cheekbone region, and then develops over time to the orbicularis oculi in the eyelid. The most common form is the typical form, while the atypical form is seen in only about 2-3% of patients with hemifacial spasm.

[0006] It has been shown that drug treatments for disorders affecting individual eyelid muscles are often unpredictable and have short-lived effects. Anticholinergic drugs, sedatives, and botulinum neurotoxins (e.g., Dysport) are examples. ® Botox ® or Xeomin® Treatment options are the most commonly used. However, these options are not optimal and are associated with serious side effects, including toxicity and undesirable facial muscle paralysis. In some cases, invasive surgery may be considered for patients who do not respond well to medication or botulinum toxin injections. Therefore, new and effective treatments for blepharospasm are constantly being tested or sought.

[0007] More specifically, botulinum neurotoxin A (BoNT / A) selectively inhibits the release of acetylcholine from presynaptic nerve endings, thereby blocking cholinergic transmission at the neuromuscular junction, inducing muscle contraction and a decrease in muscle tone, resulting in muscle relaxation at the injection site. However, the duration of action of currently available BoNT / A products is approximately 12 to 14 weeks, allowing nerve function to return to normal and the original symptoms to reappear as new nerve endings germinate. Therefore, to maintain the effect, regular repeat injections are required. Thus, considering the potential chronicity of the condition and the long-term nature of the required treatment, the frequency of BoNT / A injections is an important consideration in treating disorders affecting individual eyelid muscles (such as blepharospasm and / or unilateral hemifacial spasm). In practice, this affects direct and indirect medical costs for patients and caregivers, the logistics of injections in hospitals / clinics, and, most importantly, the patient's quality of life.

[0008] Dysport ® Approved for the treatment of blepharospasm and unilateral facial muscle spasm, the maximum total dose per eye per treatment period is 120 units. Clinicians are required to administer Dysport to the individual's eyelid muscles. ® The maximum dose per eye per treatment period is 120 units (i.e., 240 units for treating both eyes). Clinicians are forced to make difficult choices during a patient's treatment. In other words, in standard treatment regimens, clinicians must find a balance between the relatively low total amount of BoNT / A that can be administered (necessary due to the high toxicity of BoNT / A) and the effective amount for multiple different muscles and / or sites. Therefore, some muscles may be neglected, while others receive suboptimal doses of BoNT / A, resulting in unsatisfactory treatment outcomes.

[0009] Furthermore, conventional treatment regimens for these disorders are complex and can lead to underdosing by clinicians trying to avoid toxicity to patients. Therefore, there is a need for a convenient, safe, and effective single-dose unit, along with appropriate guidelines on the number of units that can be applied to the eyelid muscles during treatment (e.g., including the number of injection sites per muscle), without causing patient toxicity.

[0010] In summary, there is a need for an improved treatment approach to treat disorders affecting individual eyelid muscles (such as blepharospasm and / or unilateral facial muscle spasm), which would allow for a personalized, patient-centered approach to tailor treatment to the target clinical pattern, allow for different combinations of injections into muscles and / or sites based on the distribution, extent, and severity of the disorder, while avoiding toxicity and providing more durable treatment (and thus reducing the frequency of administration).

[0011] The present invention overcomes one or more of the above-mentioned problems. Summary of the Invention

[0012] The inventors have surprisingly discovered that modified BoNT / A is particularly useful in treating disorders affecting individual eyelid muscles, such as blepharospasm and / or unilateral facial muscle spasm. Modified BoNT / A may include a BoNT / A light chain and translocation domain, as well as a BoNT / B receptor-binding domain (H... C This results in increased retention of modified BoNT / A at the application site (reduced diffusion away from the application site) and / or increased duration of action (e.g., 6-9 months).

[0013] Advantageously, when used with unmodified BoNT / A (e.g., Dysport) ® Compared to [previous type], the modified BoNT / A exhibits improved security. This improved security characteristic can be represented by the high security ratio of the modified BoNT / A described herein.

[0014] Based on the preclinical data presented in this paper, it has been shown that higher total doses of modified BoNT / A can be administered to individuals, while achieving the same results as unmodified BoNT / A (e.g., Dysport) at such high doses. ® Similar safety profiles. Therefore, in the treatment of disorders affecting individual eyelid muscles (e.g., blepharospasm and / or unilateral facial muscle spasm) before reaching the maximum total dose, more modified BoNT / A can be injected and / or more muscles and / or sites can be injected. This is an important and advantageous finding and provides improved treatment for such disorders, while offering clinicians a wider range of treatment options. When compared with unmodified BoNT / A (e.g., Dysport) ® Compared to conventional treatments, the treatment can be improved because it provides more durable treatment (thus reducing the frequency of administration) and / or can be customized to the individual and / or improve the individual's quality of life. Therefore, the treatment of the present invention is improved compared to conventional treatment regimens.

[0015] Furthermore, as described in Examples 11 and 22, these examples summarize the results of clinical trials in which the unit dose and total dose of the modified BoNT / A (SEQ ID NO: 6, converted to double-stranded form) for facial injection were escalated, demonstrating that the molecule still has a favorable range for continued dose escalation while maintaining safety and efficacy. Notably, clinical evaluation of dose escalation data according to Example 22 showed that continued escalation of the unit dose to 4,000 pg (total dose of 64,000 pg) was well tolerated and still below the maximum dose. Based on these findings, it is believed that higher unit doses can be administered to each muscle without adverse reactions. Furthermore, given that the toxin does not spread systemically, it is believed that up to 4-5 times the higher unit dose (Example 22) can be administered without safety concerns.

[0016] Therefore, clinicians are able to tailor treatment plans to individual patients because they know that a total dose of 240,000 pg (+ / - 10%) can be administered without concern for toxicity, thereby treating additional muscles in the individual and / or ensuring that each muscle and / or its site receives an effective dose.

[0017] Therefore, as described above (for example) Figure 8 As shown in Figure 9), select a unit dose of up to 15,000 pg (±10%) and apply it to the facial area up to 16 times for the treatment of facial dystonia as described herein. Therefore, the total dose for a single treatment application will be up to 240,000 pg (±10%, e.g., 264,000 pg).

[0018] The preferred patient groups were represented by patients with blepharospasm who received doses of 5,000 pg, 7,000 pg, or 10,000 pg, with six doses administered to each eye. Thus, the total doses for these groups were 35,000 pg and 50,000 pg, respectively.

[0019] Therefore, this invention provides a convenient, safe, and effective single unit dose, as well as a total (maximum) dose that can be safely administered in a single treatment. The invention also provides corresponding guidance on the number of times the said unit dose can be administered to the muscle without causing patient toxicity (e.g., including the number of intramuscular injection sites per muscle). Therefore, treating disorders affecting individual eyelid muscles (e.g., blepharospasm and / or unilateral hemifacial spasm) according to the invention is much simpler for clinicians and helps avoid underdosing and / or overdosing. Furthermore, the treatment methods of the invention are more tailored to the patient's needs compared to conventional treatments, resulting in greater patient satisfaction. Detailed Implementation

[0020] Therefore, the present invention predicts the ability to safely administer a dose of modified BoNT / A (as described herein) at a total dose of up to 264,000 pg. As described below, this can be achieved while using different 'unit doses', while continuing to administer the total dose of up to 264,000 pg.

[0021] The broad aspect of this invention provides: - A modified botulinum neurotoxin A (BoNT / A) for treating individual blepharospasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face; - A method for treating blepharospasm in an individual, wherein the method includes administering modified BoNT / A via intramuscular injection at multiple sites on the individual's face; - Use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating individual blepharospasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face; The modified BoNT / A is administered in a unit dose comprising more than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0022] Other broad aspects of the invention provide: - A modified botulinum neurotoxin A (BoNT / A) in a method for treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face. - A method for treating typical hemifacial spasm, the method comprising administering modified BoNT / A via intramuscular injection at multiple sites on an individual's face; - Use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for the treatment of typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face; The modified BoNT / A is administered in a unit dose comprising more than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0023] Other broad aspects of the invention provide: - A modified botulinum neurotoxin A (BoNT / A) in a method for treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face. - A method for treating atypical hemifacial spasm, the method comprising administering modified BoNT / A via intramuscular injection at multiple sites on an individual's face; - Use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for the treatment of atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face; The modified BoNT / A is administered in a unit dose comprising more than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0024] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for a method of treating blepharospasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: i) Medial superior orbicularis oculi muscle (e.g., in the pre-septal portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the pre-septal portion); ii) Orbicularis oculi muscle of the superior orbit; iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); iv) Orbicularis oculi muscle of the outer orbit; v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and vi) the orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the medial inferior orbicularis oculi muscle, preferably the pre-orbital portion); and ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral inferior orbicularis oculi muscle, preferably the pre-orbital portion); and / or c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and ii) A region on the protractor supercilii muscle near the individual's first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0025] On the one hand, a method for treating individual blepharospasm is provided, the method comprising administering modified botulinum neurotoxin A (BoNT / A) via intramuscular injection at multiple sites on the individual's face, the method comprising: a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: i) Medial superior orbicularis oculi muscle (e.g., in the pre-septal portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the pre-septal portion); ii) Orbicularis oculi muscle of the superior orbit; iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); iv) Orbicularis oculi muscle of the outer orbit; v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and vi) the orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the medial inferior orbicularis oculi muscle, preferably the pre-orbital portion); and ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral inferior orbicularis oculi muscle, preferably the pre-orbital portion); and / or c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and ii) A region on the protractor supercilii muscle near the individual's first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0026] On the one hand, the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm is provided, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the treatment comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the preorbital portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the preorbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the medial inferior orbicularis oculi muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral inferior orbicularis oculi muscle, preferably the pre-orbital portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A region on the protractor supercilii muscle near the individual’s first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0027] As described above, a total dose of up to 264,000 pg can be achieved while continuing to administer the total dose of up to 264,000 pg. Therefore, although the foregoing aspects relate to unit doses greater than 8,000 ng, this total dose can also be achieved using unit dose values ​​of 8,000 ng and below (e.g., 7,000 ng) (see aspects below). Note that when administered to multiple facial sites (including both eyes for the treatment of blepharospasm), 12-16 unit doses are typically administered; such multiple unit doses (e.g., 7 ng) typically produce a total dose greater than 88,000 pg, which will be reflected in aspects below.

[0028] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for a method of treating blepharospasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: i) Medial superior orbicularis oculi muscle (e.g., in the pre-septal portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the pre-septal portion); ii) Orbicularis oculi muscle of the superior orbit; iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); iv) Orbicularis oculi muscle of the outer orbit; v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and vi) the orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the medial inferior orbicularis oculi muscle, preferably the pre-orbital portion); and ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral inferior orbicularis oculi muscle, preferably the pre-orbital portion); and / or c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and ii) A region on the protractor supercilii muscle near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0029] On one hand, a method for treating blepharospasm in an individual is provided, the method comprising administering modified botulinum neurotoxin A (BoNT / A) via intramuscular injection at multiple sites on the individual's face, the method comprising: a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: i) Medial superior orbicularis oculi muscle (e.g., in the pre-septal portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the pre-septal portion); ii) Orbicularis oculi muscle of the superior orbit; iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); iv) Orbicularis oculi muscle of the outer orbit; v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and vi) the orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the medial inferior orbicularis oculi muscle, preferably the pre-orbital portion); and ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral inferior orbicularis oculi muscle, preferably the pre-orbital portion); and / or c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and ii) A region on the protractor supercilii muscle near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0030] On the one hand, the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm is provided, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the treatment comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the preorbital portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the preorbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the medial inferior orbicularis oculi muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral inferior orbicularis oculi muscle, preferably the pre-orbital portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A region on the protractor supercilii muscle near the individual’s first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0031] In this disclosure, the injection site “outer orbital orbicularis oculi” is referred to in the context of the injection site “superior orbicularis oculi”, for example, because the site “outer orbital orbicularis oculi” is closer to the upper eyelid than the lower eyelid. That is, in any aspect of the embodiments described herein (whether for the treatment of blepharospasm, typical hemifacial spasm, or atypical hemifacial spasm), the following terms referenced in (1) may be used synonymously with the following terms referenced in (2): (1) "At up to six different injection sites near the orbicularis oculi muscle of an individual’s first (and / or second) eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the preorbital portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the preorbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) Lateral superior tarsal plate anterior orbital orbicularis oculi muscle; (2) "At up to six different injection sites near the individual's first (and / or second) eye, on the superior orbicularis oculi muscle and / or the lateral orbital orbicularis oculi muscle, at each injection site, a unit dose of modified BoNT / A is applied, wherein said up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the preorbital portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the preorbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) Lateral superior tarsal plate anterior orbital orbicularis oculi muscle.

[0032] The modified BoNT / A can preferably be administered via intramuscular injection at at least six different sites on an individual's face. In other words, the modified BoNT / A can preferably be administered via intramuscular injection to at least six different sites on an individual's face. Furthermore, the number of different injection sites for administering a unit dose can preferably be at least six.

[0033] The injection protocol of this invention allows clinicians to adjust the injection site based on the muscle involvement pattern of the participant's blepharospasm, thereby determining the injection location. It also reduces the risk of ptosis.

[0034] If the pre-tarsal muscles of the upper eyelid are affected, it is preferable to perform up to two injections in the pre-tarsal portion of the orbicularis oculi muscle of the upper eyelid. This approach preferably avoids the upper eyelid sulcus, thus reducing the likelihood of ptosis. If the corrugator supercilii / depressor supercilii muscles are affected, it is preferable to perform up to two injections between each eyebrow.

[0035] A method for treating blepharospasm may also include: (a) At up to six different injection sites near the orbicularis oculi muscle of the second eye of the individual, a unit dose of modified BoNT / A is applied to each injection site, wherein said up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the preorbital portion or orbital portion of the medial superior orbicularis oculi muscle, preferably the preorbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the lateral superior orbicularis oculi muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the second eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the medial inferior orbicularis oculi muscle, preferably the pre-orbital portion); and (ii) Lateral inferior orbicularis oculi muscle; and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's second eye; and (ii) A part on the protruding supercilium muscle near the individual's second eye.

[0036] When applied to a “second eye” affected by blepharospasm, the method of the present invention preferably includes the following prerequisite: the depressor supercilii muscle receives a single unit dose of modified BoNT / A.

[0037] The modified BoNT / A can preferably be administered via intramuscular injection at at least six different sites on an individual's face. In other words, the modified BoNT / A can preferably be administered via intramuscular injection to at least six different sites on an individual's face. Furthermore, the number of different injection sites for administering a unit dose can preferably be at least six.

[0038] A method for treating blepharospasm may preferably include: (a) A unit dose of modified BoNT / A is applied to the lateral superior orbicularis oculi muscle near the first eye of the individual (e.g., in the preorbital portion or orbital portion of the muscle, preferably the lateral superior orbicularis oculi muscle). (b) Applying a unit dose of the modified BoNT / A to the medial superior orbicularis oculi muscle near the individual's first eye (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the medial superior orbicularis oculi pre-orbital portion); and (c) A unit dose of modified BoNT / A is applied to the lateral inferior orbicularis oculi muscle near the individual’s first eye (e.g., in the preorbital septum or orbital portion of the muscle, preferably the lateral inferior orbicularis oculi muscle).

[0039] In other words, a preferred method for treating blepharospasm may include applying a unit dose of modified BoNT / A to the following sites: (a) The lateral superior orbicularis oculi muscle near the individual's first eye (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the lateral superior orbital septum pre-orbicularis oculi muscle); (b) The medial superior orbicularis oculi muscle near the individual's first eye (e.g., in the pre-orbital septum or orbital portion of said muscle, preferably the medial superior pre-orbital septum orbicularis oculi muscle); and (c) The lateral inferior orbicularis oculi muscle near the individual's first eye (e.g., in the preorbital septum or orbital portion of the muscle, preferably the lateral inferior orbicularis oculi muscle).

[0040] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for a method of treating blepharospasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg, preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0041] In a related aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for the treatment of blepharospasm in an individual, wherein the treatment duration is longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0042] In a related aspect, the present invention provides a method for treating individual blepharospasm, wherein the modified BoNT / A is administered via intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye. The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0043] In a related aspect, the present invention provides a method for treating individual blepharospasm, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0044] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating individual blepharospasm, comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0045] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating blepharospasm in individuals, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0046] As described above, a total dose of up to 264,000 pg can be achieved while continuing to administer the total dose of up to 264,000 pg. Therefore, although the foregoing aspects relate to unit doses greater than 8,000 ng, this total dose can also be achieved using unit dose values ​​of 8,000 ng and below (e.g., 7,000 ng) (see aspects below). Note that when administered to multiple facial sites (including both eyes for the treatment of blepharospasm), 12-16 unit doses are typically administered; such multiple unit doses (e.g., 7 ng) typically produce a total dose greater than 88,000 pg, which will be reflected in aspects below.

[0047] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for a method of treating blepharospasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0048] In a related aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for the treatment of blepharospasm in an individual, wherein the treatment duration is longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0049] In a related aspect, the present invention provides a method for treating individual blepharospasm, wherein the modified BoNT / A is administered via intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0050] In a related aspect, the present invention provides a method for treating individual blepharospasm, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0051] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating individual blepharospasm, comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0052] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating blepharospasm in individuals, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the individual's first eye; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0053] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for the treatment of typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A region on the protractor supercilii muscle near the individual's first eye; and / or (d) Administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0054] On one hand, a method for treating typical hemifacial spasm is provided, the method comprising administering modified BoNT / A via intramuscular injection at multiple sites on an individual's face, the method comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A region on the protractor supercilii muscle near the individual's first eye; and / or (d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0055] On the one hand, the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm is provided, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the treatment comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) An injection site on the protractor supercilii muscle near the individual's first eye; and / or (d) Administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0056] As described above, a total dose of up to 264,000 pg can be achieved while continuing to administer the total dose of up to 264,000 pg. Therefore, although the foregoing aspects relate to unit doses greater than 8,000 ng, this total dose can also be achieved using unit dose values ​​of 8,000 ng and below (e.g., 7,000 ng) (see aspects below). Note that when administered to multiple facial sites (including both eyes for the treatment of blepharospasm), 12-16 unit doses are typically administered; such multiple unit doses (e.g., 7 ng) typically produce a total dose greater than 88,000 pg, which will be reflected in aspects below.

[0057] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for the treatment of typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A region on the protractor supercilii muscle near the individual's first eye; and / or (d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0058] On one hand, a method for treating typical hemifacial spasm is provided, the method comprising administering modified BoNT / A via intramuscular injection at multiple sites on an individual's face, the method comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A region on the protractor supercilii muscle near the individual's first eye; and / or (d) Administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0059] On the one hand, the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm is provided, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the treatment comprising: (a) At up to six different injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to six different injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) At up to two distinct injection sites near the orbicularis oculi muscle of the individual's first eye, a unit dose of modified BoNT / A is applied to each injection site, wherein the up to two distinct injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or (c) Applying a unit dose of the modified BoNT / A to at most two different injection sites, said two different injection sites being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A region on the protractor supercilii muscle near the individual's first eye; and / or (d) Administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0060] The modified BoNT / A can preferably be administered via intramuscular injection at at least six different sites on an individual's face. In other words, the modified BoNT / A can preferably be administered via intramuscular injection to at least six different sites on an individual's face. Furthermore, the number of different injection sites for administering a unit dose can preferably be at least six.

[0061] Preferred methods for treating typical unilateral facial muscle spasm include: (a) A unit dose of modified BoNT / A is applied to the lateral superior orbicularis oculi muscle near the first eye of the individual (e.g., in the preorbital portion or orbital portion of the muscle, preferably the lateral superior orbicularis oculi muscle). (b) Applying a unit dose of the modified BoNT / A to the medial superior orbicularis oculi muscle near the individual's first eye (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the medial superior orbicularis oculi pre-orbital portion); and (c) A unit dose of modified BoNT / A is applied to the lateral inferior orbicularis oculi muscle near the individual’s first eye (e.g., in the preorbital septum or orbital portion of the muscle, preferably the lateral inferior orbicularis oculi muscle).

[0062] In other words, a preferred method for treating typical hemifacial spasm may include administering a unit dose of modified BoNT / A to the following sites: (a) The lateral superior orbicularis oculi muscle near the individual's first eye (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the lateral superior orbital septum pre-orbicularis oculi muscle); (b) The medial superior orbicularis oculi muscle near the individual's first eye (e.g., in the pre-orbital septum or orbital portion of said muscle, preferably the medial superior pre-orbital septum orbicularis oculi muscle); and (c) The lateral inferior orbicularis oculi muscle near the individual's first eye (e.g., in the preorbital septum or orbital portion of the muscle, preferably the lateral inferior orbicularis oculi muscle).

[0063] On the other hand, a modified botulinum neurotoxin A (BoNT / A) is provided in a method for treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 240,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0064] In a related aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for treating typical hemifacial spasm in an individual, wherein the treatment duration is longer than that of unmodified BoNT / A (e.g., SEQ ID NO:2 [such as the double-stranded form of SEQ ID NO:2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle of the eye near the eye affected by unilateral hemifacial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0065] In a related aspect, the present invention provides a method for treating typical unilateral facial muscle spasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0066] In a related aspect, the present invention provides a method for treating typical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0067] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0068] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0069] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for the treatment of atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., in the preorbital septum portion or orbital portion of the muscle, preferably the orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) An injection site for the depressor supercilii muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0070] On one hand, a method for treating atypical hemifacial spasm is provided, the method comprising administering modified BoNT / A via intramuscular injection at multiple sites on an individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the preorbital septum portion or orbital portion of the muscle, preferably the orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) A part of the depressor supercilii muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0071] On the one hand, the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating atypical hemifacial spasm is provided, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the treatment comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) An injection site for the depressor supercilii muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and BoNT / B receptor binding domain (H C (structural domain).

[0072] On the other hand, a modified botulinum neurotoxin A (BoNT / A) is provided in a method for treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by the said hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by the said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0073] In a related aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for the treatment of atypical hemifacial spasm in an individual, wherein the treatment duration is longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by the said hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by the said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0074] In a related aspect, the present invention provides a method for treating atypical hemifacial spasm in an individual, wherein the modified BoNT / A is administered via intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0075] In a related aspect, the present invention provides a method for treating atypical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0076] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating atypical hemifacial spasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0077] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating atypical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (e.g., greater than 24,100 pg; e.g., greater than 35,000 pg; preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 264,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0078] As described above, a total dose of up to 264,000 pg can be achieved by using different 'unit doses' while continuing to administer a total dose of up to 264,000 pg. Therefore, while the foregoing aspects involve unit doses greater than 8,000 ng, this total dose can also be achieved using unit dose values ​​of 8,000 ng and below (e.g., 7,000 ng) (see aspects below). Note that when administered to multiple facial sites (including both eyes for the treatment of blepharospasm), 12-16 unit doses are typically required, and such multiple unit doses (e.g., 7 ng) will generally produce a total dose greater than 88,000 pg, which will be reflected in aspects below.

[0079] On the other hand, a modified botulinum neurotoxin A (BoNT / A) is provided in a method for treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0080] In a related aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for treating typical hemifacial spasm in an individual, wherein the treatment duration is longer than that of unmodified BoNT / A (e.g., SEQ ID NO:2 [such as the double-stranded form of SEQ ID NO:2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle of the eye near the eye affected by unilateral hemifacial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0081] In a related aspect, the present invention provides a method for treating typical unilateral facial muscle spasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0082] In a related aspect, the present invention provides a method for treating typical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0083] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0084] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating typical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Apply a unit dose of modified BoNT / A to the lateral superior orbicularis oculi muscle (preferably the lateral superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle (preferably the medial superior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial muscle spasm; c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the eye affected by unilateral facial spasm; and d) Administer one or more units of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0085] On one hand, a modified botulinum neurotoxin A (BoNT / A) is provided for the treatment of atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., in the preorbital septum portion or orbital portion of the muscle, preferably the orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) An injection site for the depressor supercilii muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. The total dose administered during treatment was greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0086] On one hand, a method for treating atypical hemifacial spasm is provided, the method comprising administering modified BoNT / A via intramuscular injection at multiple sites on an individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the preorbital septum portion or orbital portion of the muscle, preferably the orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) A part of the depressor supercilii muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0087] On the one hand, the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating atypical hemifacial spasm is provided, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the treatment comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The medial superior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbicularis oculi muscle (e.g., in the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle (e.g., the pre-orbital portion or orbital portion of the muscle, preferably the pre-orbital portion); and (ii) the lateral inferior orbicularis oculi muscle (e.g., the pre-septal or orbital portion of the muscle, preferably the pre-septal portion); and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) An injection site for the depressor supercilii muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg (preferably greater than 75,000 pg) and at most 264,000 pg (e.g., at most 240,000 pg) of modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0088] On the other hand, a modified botulinum neurotoxin A (BoNT / A) is provided in a method for treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on an individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0089] In a related aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for the treatment of atypical hemifacial spasm in an individual, wherein the treatment duration is longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by the said hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by the said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0090] In a related aspect, the present invention provides a method for treating atypical hemifacial spasm in an individual, wherein the modified BoNT / A is administered via intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0091] In a related aspect, the present invention provides a method for treating atypical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0092] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating atypical hemifacial spasm in an individual, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0093] In one aspect, the present invention provides the use of modified botulinum neurotoxin A (BoNT / A) in the preparation of a medicament for treating atypical hemifacial spasm in an individual, with a treatment duration longer than that of unmodified BoNT / A (e.g., SEQ ID NO: 2 [such as the double-stranded form of SEQ ID NO: 2]), wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, comprising: a) Applying a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); and b) Optionally, administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg; more preferably 6500 pg to 7500 pg) of modified BoNT / A. Among them, the total dose of modified BoNT / A administered during treatment was greater than 82,500 pg and up to 264,000 pg (e.g., up to 240,000 pg), and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

[0094] Throughout this disclosure, mentioning a total dose of more than 24,000 pg of modified BoNT / A during treatment may mean a total dose of more than 24,100 pg of modified BoNT / A during treatment. More preferably, mentioning a total dose of more than 24,000 pg of modified BoNT / A during treatment may mean a total dose of more than 35,000 pg of modified BoNT / A during treatment. Particularly preferably, mentioning a total dose of more than 24,000 pg of modified BoNT / A during treatment may mean a total dose of more than 75,000 pg of modified BoNT / A during treatment.

[0095] The term “typical hemifacial spasm” may be used interchangeably with the term “hemifacial spasm” in this disclosure.

[0096] The term "longer duration of blepharospasm in the treated individual compared to the duration of treatment with unmodified BoNT / A" can refer to a longer period (e.g., 6-9 months) of relief of one or more symptoms of the disorder after application of the modified BoNT / A of the present invention, compared to the application of unmodified BoNT / A. This relief can be determined by comparison with equivalent control individuals treated with unmodified BoNT / A who exhibited equivalent symptoms. Within a substantially similar (e.g., identical) time period in which the severity of one or more symptoms in the control individuals was before treatment with unmodified BoNT / A, individuals treated with the modified BoNT / A according to the present invention may exhibit equivalent improvement of one or more symptoms by at least 5%, 10%, 25%, or 50% compared to the severity of one or more symptoms before treatment with modified BoNT / A. The unmodified BoNT / A is preferably in double-stranded form, SEQ ID NO: 2.

[0097] The term "duration of typical hemifacial spasm in the treated individual is longer than the treatment duration with unmodified BoNT / A" can refer to a longer period of time (e.g., 6-9 months) of reduction in one or more symptoms of the disorder after application of the modified BoNT / A of the present invention, compared to the application of unmodified BoNT / A. This reduction can be determined by comparison with equivalent control individuals treated with unmodified BoNT / A who exhibit equivalent symptoms. Within a substantially the same (e.g., the same) time period in which the severity of one or more symptoms in the control individuals is comparable to that before treatment with unmodified BoNT / A, individuals treated with the modified BoNT / A according to the present invention may exhibit equivalent improvement in one or more symptoms of at least 5%, 10%, 25%, or 50% compared to the severity of one or more symptoms before treatment with modified BoNT / A.

[0098] The term "duration of atypical hemifacial spasm in the treated individual longer than the duration of treatment with unmodified BoNT / A" can refer to a longer period of time (e.g., 6-9 months) of reduction in one or more symptoms of the disorder after application of the modified BoNT / A of the present invention, compared to the application of unmodified BoNT / A. This reduction can be determined by comparison with equivalent control individuals treated with unmodified BoNT / A who exhibit equivalent symptoms. Within a substantially similar (e.g., identical) time period in which the severity of one or more symptoms in the control individuals is compared to the severity of one or more symptoms before treatment with unmodified BoNT / A, individuals treated with the modified BoNT / A according to the present invention may exhibit equivalent improvement in one or more symptoms of at least 5%, 10%, 25%, or 50% compared to the severity of one or more symptoms before treatment with modified BoNT / A.

[0099] The unit dose can be greater than 8000 pg and up to 16,500 pg (preferably up to 15,000 pg) of modified BoNT / A. In other words, the unit dose can be greater than 8000 pg and up to 16,500 pg (preferably up to 15,000 pg) of modified BoNT / A. The upper limit of the unit dose range can be 16,500, 16,000, 15,000, 14,000, 13,000, 12,000, 11,000, 10,000 or 9,000 pg of modified BoNT / A, preferably, the upper limit is 15,000 pg. The lower limit of the unit dose range can be 8,100, 8,300, 8,500, 8,700, 8,900, 9,100, 9,300, 9,500, 9,700 or 9,900 pg of modified BoNT / A, preferably about 9,000 pg.

[0100] The unit dose of modified BoNT / A can be from 8,100 to 16,500 pg. For example, the unit dose of modified BoNT / A can be from 8,500 to 15,000 pg. Preferably, the unit dose of modified BoNT / A can be greater than 8,000 pg and at most 11,000 pg, and particularly preferably, in the range of 5,000 to 10,000 pg.

[0101] The unit dose can be 8100 pg, 8500 pg, 9000 pg, 9500 pg, 10000 pg, 11500 pg, 12000 pg, 12500 pg, 13000 pg, 13500 pg, 14000 pg, 14500 pg, 15000 pg, 15500 pg, 16000 pg, or 16500 pg of modified BoNT / A. For example, the unit dose can be 8500 pg, 9000 pg, 9500 pg, or 10000 pg. Particularly suitable unit doses can be about 10000 pg or about 15000 pg.

[0102] The unit dose can be greater than 8000 pg and at most 12000 pg of modified BoNT / A. For example, the unit dose can be 8500 pg to 11500 pg of modified BoNT / A. The unit dose can be 9000 pg to 11000 pg of modified BoNT / A. A particularly preferred unit dose can be about 10000 pg (e.g., 10000 pg ± 10%) of modified BoNT / A, for example, the unit dose can be 10000 pg of modified BoNT / A.

[0103] The unit dose can be 13,500-16,500 pg of modified BoNT / A. For example, the unit dose can be 14,000 pg to 16,000 pg of modified BoNT / A. The unit dose can be 14,500 to 15,500 pg of modified BoNT / A. A particularly preferred unit dose can be about 15,000 pg (e.g., 15,000 pg ± 10%) of modified BoNT / A, for example, the unit dose can be 15,000 pg of modified BoNT / A.

[0104] As described above, a total dose of up to 264,000 pg can be achieved while continuing to administer the total dose of up to 264,000 pg. Therefore, although the foregoing aspects relate to unit doses greater than 8,000 ng, this total dose can also be achieved using unit dose values ​​of 8,000 ng and below (e.g., 7,000 ng) (see examples of unit doses below).

[0105] The unit dose can be greater than 1754 pg to 8000 pg of modified BoNT / A. In other words, the unit dose can be greater than 1754 pg and at most 8000 pg of modified BoNT / A. The upper limit of the unit dose range can be 8,000, 7,000, 6,000, 5,000, 4,000, 3,000, 2,000 or 1,000 pg of modified BoNT / A, preferably 5,000 pg. The lower limit of the unit dose range can be 1,800, 2,000, 2,500, 3,000 or 4,000 pg of modified BoNT / A, preferably 1,800 pg. The unit dose of modified BoNT / A can be selected from: 1,800 to 8,000 pg, 2,000 to 6,000 pg, and most preferably 3,000 to 6,000 pg. The unit dose of modified BoNT / A can be 4,500 to 5,500 pg of modified BoNT / A, for example, 4,900 to 5,100 pg.

[0106] The unit dose can be greater than 1800 pg of modified BoNT / A. The unit dose can be greater than 1800 pg and up to 7000 pg of modified BoNT / A, for example, greater than 1800 pg and up to 6000 pg of modified BoNT / A. The unit dose can be greater than 2000 pg and up to 5000 pg of modified BoNT / A.

[0107] The unit dose can be greater than 2555 pg. For example, the unit dose can be greater than 2555 pg and up to 8000 pg of modified BoNT / A, such as greater than 2555 pg and up to 6000 pg.

[0108] The unit dose can be 5500-9000 pg of modified BoNT / A. For example, the unit dose can be 6000 pg to 8000 pg of modified BoNT / A. The unit dose can be 6500 to 7500 pg of modified BoNT / A. A particularly preferred unit dose can be about 7000 pg (e.g., 7000 pg ± 10%) of modified BoNT / A, for example, the unit dose can be 7000 pg of modified BoNT / A.

[0109] The unit dose can be 2000 pg, 2500 pg, 3000 pg, 4000 pg, 4500 pg, 5000 pg, 5500 pg, 6000 pg, 6500 pg, 7000 pg, 7500 pg or 8000 pg modified BoNT / A.

[0110] The unit dose can be 2000 to 3500 pg of modified BoNT / A. For example, the unit dose can be 2250 pg to 3250 pg of modified BoNT / A. The unit dose can be about 2500 pg (e.g., 2500 pg ± 10%) of modified BoNT / A. For example, the unit dose can be 2500 pg of modified BoNT / A. The unit dose can be about 3000 pg (e.g., 3000 pg ± 10%) of modified BoNT / A.

[0111] The unit dose can be 3500-5500 pg of modified BoNT / A. For example, the unit dose can be 3800 pg to 4200 pg of modified BoNT / A. The unit dose can be 4800 to 5200 pg of modified BoNT / A. The unit dose can be about 4000 pg (e.g., 4000 pg ± 10%) of modified BoNT / A. The unit dose can be about 5000 pg (e.g., 5000 pg ± 10%) of modified BoNT / A, for example, the unit dose can be 5000 pg of modified BoNT / A.

[0112] The unit dose can be at least 240.4 pg, 500 pg, 1,000 pg, 2,000 pg, 3,000 pg or 4,000 pg, for example at least 1,000 pg of modified BoNT / A.

[0113] The unit dose can be at least 240.4 pg, 500 pg, 1,000 pg, 2,000 pg, 3,000 pg, 4,000 pg, 5,000 pg, 6,000 pg or 7,000 pg, preferably at least 4,000 pg of modified BoNT / A.

[0114] The upper limit of the unit dose of the present invention can be determined based on the total dose administered during treatment and the number and / or location of the muscles to which the modified BoNT / A is administered. For example, the upper limit of the unit dose may be 9,375 pg in the following cases: wherein the total dose administered during treatment of blepharospasm is up to 75,000 pg of modified BoNT / A, and the administration includes: (i) administering a (single) unit dose to the lateral superior orbicularis oculi muscle near the individual's first eye; (ii) administering a (single) unit dose to the medial superior orbicularis oculi muscle near the first eye; (iii) administering a (single) unit dose to the lateral inferior orbicularis oculi muscle near only the first eye; (iv) administering two unit doses to the frontalis muscle near only the first eye; (v) administering two unit doses to the corrugator supercilii muscle near only the first eye; and (vi) administering a (single) unit dose to the depressor supercilii muscle (e.g., eight unit doses at multiple sites). If the additional administration includes: (i) administering a (single) unit dose to the lateral superior orbicularis oculi muscle of the second eye closest to the individual; (ii) administering a (single) unit dose to the medial superior orbicularis oculi muscle of the second eye closest to the individual; (iii) administering a (single) unit dose to the lateral inferior orbicularis oculi muscle of the second eye closest to the individual; (iv) administering two unit doses to the frontalis muscle of the second eye closest to the individual; and (v) administering two unit doses to the corrugator supercilii muscle of the second eye closest to the individual (e.g., an additional seven unit doses, making the total number of unit doses 15), the maximum may be 5,000 pg.

[0115] The unit dose can be from 240 pg to 8,000 pg of modified BoNT / A, wherein the modified BoNT / A comprises a BoNT / A light chain and a translocation domain, as well as a BoNT / B receptor-binding domain (H). C(Structural domain). The upper limit of the unit dose range can be 7,500, 7,000, 6,500, 6,000, 5,500, 5,000, 4,800, 4,500, 4,000, 3,500, 3,000, 2,500, 2,400, 2,000, 1,500, or 1,250 pg of modified BoNT / A. The upper limit of the unit dose range can be 5,500, 5,000, or 4,800 pg of modified BoNT / A. Preferably, the upper limit of the unit dose range can be 5,000 pg of modified BoNT / A. The lower limit of the unit dose range can be 300, 400, 500, 600, 700, 800, 900, 1,000, 1,500, 2,000, 2,500, 3,000, 3,500, 4,000, 4,500 or 5,000 pg of modified BoNT / A, preferably 1,000 pg. The unit dose can be 1,000 pg to 6,000 pg, 1,000 pg to 5,500 pg, 1,000 pg to 5,000 pg or 1,000 pg to 4,500 pg of modified BoNT / A. The unit dose can be 1,000 pg to 4,800 pg, 1.0 pg to 4,000 pg, 1,000 pg to 2,400 pg or 1,000 pg to 2,000 pg.

[0116] The unit dose can be 1,500-5,000 pg of modified BoNT / A, preferably 2,000-4,500 pg. Examples of suitable unit doses include about 2,500 pg (e.g., 2,000 pg ± 10%) of modified BoNT / A; and about 4,000 pg (e.g., 4,000 pg ± 10%) of modified BoNT / A. This unit dose is particularly suitable for treating blepharospasm (whether bilateral or unilateral).

[0117] When implementing the treatment regimen of the present invention, the total dose applied may be up to 264,000, 260,000, 250,000, 240,000, 230,000, 220,000, 210,000, 200,000, 190,000, 180,000, 170,000, 160,000, 150,000, 140,000, 130,000, 120,000, 115,000, 110,000, 100,000 or 90,000 pg of modified BoNT / A, preferably up to 260,000 pg of modified BoNT / A. Therefore, the upper limit of the total dose can be 264,000, 260,000, 250,000, 240,000, 230,000, 220,000, 210,000, 200,000, 190,000, 180,000, 170,000, 160,000, 150,000, 140,000, 130,000, 120,000, 115,000, 110,000, 100,000 or 90,000 pg of modified BoNT / A, preferably 260,000 pg of modified BoNT / A. The lower limit of the total dose range can be 90,000 pg, 95,000 pg, 100,000 pg, 105,000 pg, 111,000 pg or 115,000 pg modified BoNT / A.

[0118] For example, the lower limit of the total dose can be 90,000, 80,000, 70,000, 60,000, 50,000, 40,000, 30,000, or 25,000 pg of modified BoNT / A.

[0119] The total dose of modified BoNT / A can be up to 260,000 pg (preferably up to 240,000 pg). The upper limit of the total dose range can be 260,000, 250,000, 240,000, 230,000, 220,000, 210,000, 200,000, 190,000, 180,000, 170,000, 160,000, 150,000, 140,000, 130,000, 120,000, 110,000, 100,000, 90,000, 80,000, 70,000, 60,000, 50,000, 40,000, 30,000, or 25,000 pg of modified BoNT / A (preferably, the upper limit is 160,000 pg of modified BoNT / A). The lower limit of the unit dose range can be 16,000, 17,000, 18,000, 19,000, 20,000, 21,000, 22,000, 23,000 or 24,000 pg of modified BoNT / A.

[0120] The total dose administered when implementing the treatment regimen of the present invention may be from 16,000 pg to 264,000 pg of modified BoNT / A. The total dose may be from 20,000 to 264,000 pg, 30,000 to 264,000 pg, 40,000 to 264,000 pg, 50,000 to 264,000 pg, 60,000 to 264,000 pg, 80,000 to 264,000 pg, or 90,000 to 264,000 pg of modified BoNT / A (preferably 50,000 to 264,000 pg of modified BoNT / A). The total dose can be 20,000 to 240,000 pg, 30,000 to 240,000 pg, 40,000 to 240,000 pg, 50,000 to 240,000 pg, 60,000 to 240,000 pg, 70,000 to 240,000 pg, 80,000 to 240,000 pg, or 90,000 to 240,000 pg of modified BoNT / A (preferably 50,000 to 240,000 pg of modified BoNT / A).

[0121] The preferred total dose may be greater than 88,000 pg and up to 264,000 pg of modified BoNT / A. For example, the total dose may be greater than 88,000 pg and up to 240,000 pg of modified BoNT / A.

[0122] A total dose of modified BoNT / A of 16,000 pg to 264,000 pg can be administered to an individual (e.g., via multiple unit doses as described herein). For example, the total dose can be 16,000 pg to 240,000 pg of modified BoNT / A. Therefore, 16,000 pg to 240,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). A particularly preferred total dose can be about 240,000 pg (e.g., 240,000 pg ± 10%) of modified BoNT / A. For example, the total dose can be 240,000 pg of modified BoNT / A. Therefore, about 240,000 pg (e.g., 240,000 pg ± 10%) of modified BoNT / A can be administered to an individual, for example, 240,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0123] The total dose administered when implementing the treatment regimen of the present invention can be from 16,000 pg to 176,000 pg of modified BoNT / A. The total dose can be from 20,000 to 176,000 pg, 30,000 to 176,000 pg, 40,000 to 176,000 pg, 50,000 to 176,000 pg, 60,000 to 176,000 pg, 70,000 to 176,000 pg, 80,000 to 176,000 pg, or 90,000 to 176,000 pg of modified BoNT / A (preferably 50,000 to 176,000 pg of modified BoNT / A). The total dose can be 20,000 to 160,000 pg, 30,000 to 160,000 pg, 40,000 to 160,000 pg, 50,000 to 160,000 pg, 60,000 to 160,000 pg, 70,000 to 160,000 pg, 80,000 to 160,000 pg, or 90,000 to 160,000 pg of modified BoNT / A (preferably 50,000 to 160,000 pg of modified BoNT / A).

[0124] Another preferred total dose may be greater than 88,000 pg and up to 176,000 pg of modified BoNT / A. For example, the total dose may be greater than 88,000 pg and up to 160,000 pg of modified BoNT / A. Examples of suitable total doses include 100,000 to 120,000 pg of modified BoNT / A, preferably 110,000 to 115,000 pg of modified BoNT / A.

[0125] Another preferred total dose may be greater than 88,000 pg and up to 124,000 pg of modified BoNT / A. For example, the total dose may be greater than 88,000 pg and up to 112,000 pg of modified BoNT / A.

[0126] A total dose of 16,000 pg to 176,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). For example, the total dose can be 16,000 pg to 160,000 pg of modified BoNT / A. Therefore, 16,000 pg to 160,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). A particularly preferred total dose can be about 160,000 pg (e.g., 160,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 160,000 pg of modified BoNT / A. Therefore, about 160,000 pg (e.g., 160,000 pg ± 10%) of modified BoNT / A can be administered to an individual, for example, 160,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0127] The total dose administered when implementing the treatment regimen of the present invention may be from 16,000 pg to 88,000 pg of modified BoNT / A. The total dose may be from 20,000 to 88,000 pg, 30,000 to 88,000 pg, 40,000 to 88,000 pg, 50,000 to 88,000 pg, 60,000 to 88,000 pg, 70,000 to 88,000 pg, or 80,000 to 88,000 pg of modified BoNT / A. The total dose can be 20,000 to 80,000 pg, 30,000 to 80,000 pg, 40,000 to 80,000 pg, 50,000 to 80,000 pg, 60,000 to 80,000 pg, 70,000 to 88,000 pg or 80,000 to 88,000 pg of modified BoNT / A.

[0128] Therefore, 16,000 pg to 88,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). For example, the total dose can be 16,000 pg to 80,000 pg of modified BoNT / A. A particularly preferred total dose can be about 80,000 pg (e.g., 80,000 pg ± 10%) of modified BoNT / A. Therefore, about 80,000 pg (e.g., 80,000 pg ± 10%) of modified BoNT / A can be administered to an individual, for example, 80,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0129] The total dose administered to an individual can be from 16,000 pg to 66,000 pg of modified BoNT / A. Therefore, 16,000 pg to 66,000 pg of modified BoNT / A can be administered to an individual (e.g., through multiple unit doses as described herein). A particularly preferred total dose can be about 60,000 pg (e.g., 60,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 60,000 pg of modified BoNT / A. Therefore, about 60,000 pg (e.g., 60,000 pg ± 10%) of modified BoNT / A can be administered to an individual, for example, 60,000 pg of modified BoNT / A can be administered to an individual (e.g., through multiple unit doses as described herein).

[0130] The total dose administered can be up to 82,500, 80,000, 78,000, 76,000, or 75,000 pg of modified BoNT / A, preferably up to 75,000 pg of modified BoNT / A. The total dose can also be about 75,000 pg (e.g., 75,000 pg ± 10%) of modified BoNT / A, for example, a total dose of 75,000 pg of modified BoNT / A. The lower limit of the range of total doses administered can be 60,000, 65,000, or 70,000 pg of modified BoNT / A (preferably 60,000 pg of modified BoNT / A).

[0131] The total dose administered can be from 70,000 pg to 82,500 pg of modified BoNT / A; for example, from 72,500 pg to 80,000 pg of modified BoNT / A, such as from 74,000 pg to 76,000 pg of modified BoNT / A. A specific total dose administered can be about 75,000 pg of modified BoNT / A.

[0132] The total dose administered can be up to 55,500, 55,000, 54,000, 53,000, 52,000, 51,000, or 50,000 pg of modified BoNT / A, preferably up to 50,000 pg of modified BoNT / A. The total dose administered can be about 50,000 pg (e.g., 50,000 pg ± 10%) of modified BoNT / A; for example, the total dose can be 50,000 pg of modified BoNT / A. The lower limit of the range of total doses administered when implementing the treatment regimen can be 30,000, 35,000, 40,000, or 45,000 pg of modified BoNT / A (preferably 30,000 pg of modified BoNT / A).

[0133] The total dose administered when implementing the treatment regimen may be from 45,000 pg to 55,000 pg of modified BoNT / A; for example, from 47,500 pg to 52,500 pg of modified BoNT / A, or from 49,000 pg to 51,000 pg of modified BoNT / A. A specific total dose administered may be about 50,000 pg of modified BoNT / A.

[0134] The total dose administered during the treatment regimen may be up to 27,500, 27,000, 26,000, or 25,000 pg of modified BoNT / A, for example, up to 25,000 pg of modified BoNT / A. The total dose administered during the treatment regimen may be approximately 25,000 pg (e.g., 25,000 pg ± 10%) of modified BoNT / A, for example, the total dose may be 25,000 pg of modified BoNT / A.

[0135] The total dose administered during the treatment regimen can be up to 99,000, 97,000, 95,000, 93,000, 91,000, or 90,000 pg of modified BoNT / A, for example, up to 90,000 pg of modified BoNT / A. The total dose administered during the treatment regimen can be about 90,000 pg (e.g., 90,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 90,000 pg of modified BoNT / A. The lower limit of the range of total doses administered can be 70,000, 75,000, 80,000, or 85,000 pg of modified BoNT / A (preferably 70,000 pg of modified BoNT / A).

[0136] The total dose administered when implementing the treatment regimen can be from 80,000 pg to 99,000 pg of modified BoNT / A; for example, from 85,000 pg to 95,000 pg of modified BoNT / A, or from 89,000 pg to 91,000 pg of modified BoNT / A. A specific total dose administered can be approximately 90,000 pg of modified BoNT / A.

[0137] The total dose administered can be up to 66,000, 65,000, 64,000, 63,000, 62,000, 61,000, or 60,000 pg of modified BoNT / A, for example, up to 60,000 pg of modified BoNT / A. The total dose can be about 60,000 pg (e.g., 60,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 60,000 pg of modified BoNT / A. The lower limit of the total dose range can be 30,000, 35,000, 40,000, 45,000, 50,000, or 55,000 pg of modified BoNT / A (preferably 35,000 pg of modified BoNT / A).

[0138] The total dose administered when implementing a treatment regimen can be up to 50,000 pg to 70,000 pg of modified BoNT / A; for example, 55,000 pg to 65,000 pg of modified BoNT / A, or 59,000 pg to 61,000 pg of modified BoNT / A. A specific total dose administered can be approximately 60,000 pg of modified BoNT / A.

[0139] The total dose administered during the treatment regimen can be up to 33,000 pg, 31,000 pg, or 30,000 pg of modified BoNT / A, for example, up to 30,000 pg of modified BoNT / A. The total dose administered can be about 30,000 pg (e.g., 30,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 30,000 pg of modified BoNT / A. The lower limit of the range of total doses administered during the treatment regimen can be 25,000, 27,000, or 29,000 pg of modified BoNT / A (preferably 25,000 pg of modified BoNT / A).

[0140] The total dose administered during the treatment regimen can be from 20,000 pg to 40,000 pg of modified BoNT / A; for example, from 25,000 pg to 35,000 pg of modified BoNT / A, or from 29,000 pg to 31,000 pg of modified BoNT / A. The total dose can also be approximately 30,000 pg of modified BoNT / A.

[0141] The total dose can be up to 30,000 pg or 25,000 pg of modified BoNT / A, for example, up to 25,000 pg of modified BoNT / A.

[0142] The total dose can be up to 165,000, 160,000, 156,000, 152,000, or 150,000 pg of modified BoNT / A, for example, up to 150,000 pg of modified BoNT / A. The total dose administered can be about 150,000 pg (e.g., 150,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 150,000 pg of modified BoNT / A. The lower limit of the total dose range can be 120,000, 130,000, or 140,000 pg of modified BoNT / A (preferably 120,000 pg of modified BoNT / A).

[0143] The total dose can be from 140,000 pg to 165,000 pg of modified BoNT / A; for example, from 145,000 pg to 160,000 pg of modified BoNT / A, such as from 148,000 pg to 152,000 pg of modified BoNT / A. A specific total dose can be about 150,000 pg of modified BoNT / A.

[0144] The total dose can be up to 111,000, 110,000, 108,000, 106,000, 104,000, 102,000, or 100,000 pg of modified BoNT / A, preferably up to 100,000 pg of modified BoNT / A. The total dose administered can be about 100,000 pg (e.g., 100,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 100,000 pg of modified BoNT / A. The lower limit of the range of total doses administered can be 60,000, 70,000, 80,000, or 90,000 pg of modified BoNT / A (preferably 60,000 pg of modified BoNT / A).

[0145] The total dose can be from 90,000 pg to 110,000 pg of modified BoNT / A; for example, from 95,000 pg to 105,000 pg of modified BoNT / A, such as from 98,000 pg to 102,000 pg of modified BoNT / A. A specific total dose can be about 100,000 pg of modified BoNT / A.

[0146] The total dose can be up to 55,000, 54,000, 52,000, or 50,000 pg of modified BoNT / A, for example, up to 50,000 pg of modified BoNT / A. The total dose can be about 50,000 pg (e.g., 50,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 50,000 pg of modified BoNT / A. The lower limit of the total dose range can be 40,000, 42,000, 44,000, 46,000, or 48,000 pg of modified BoNT / A (preferably 40,000 pg of modified BoNT / A).

[0147] The total dose can be from 40,000 pg to 55,000 pg of modified BoNT / A; for example, from 45,000 pg to 54,000 pg of modified BoNT / A, or from 48,000 pg to 52,000 pg of modified BoNT / A. A specific total dose can be about 50,000 pg of modified BoNT / A.

[0148] The total dose administered can be from 31,000 pg to 33,000 pg of modified BoNT / A. Therefore, 31,000 pg to 33,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). A specific total dose can be about 32,000 pg (e.g., 32,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 32,000 pg of modified BoNT / A. Therefore, about 32,000 pg (e.g., 32,000 pg ± 10%) of modified BoNT / A can be administered to an individual, for example, 32,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0149] The total dose administered can be 35,000 to 45,000 pg of modified BoNT / A. Therefore, 35,000 to 45,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). The total dose can also be about 40,000 pg (e.g., 40,000 pg ± 10%) of modified BoNT / A. Therefore, about 40,000 pg (e.g., 40,000 pg ± 10%) of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0150] The total dose administered may be up to 181,500, 177,000, 173,000, 167,000, or 165,000 pg of modified BoNT / A, for example, up to 165,000 pg of modified BoNT / A. The total dose administered during the treatment regimen may be approximately 165,000 pg (e.g., 165,000 pg ± 10%) of modified BoNT / A, for example, the total dose may be 165,000 pg of modified BoNT / A. The lower limit of the range of total doses administered may be 130,000, 140,000, or 150,000 pg of modified BoNT / A (preferably 130,000 pg of modified BoNT / A).

[0151] The total dose administered can be from 150,000 pg to 181,500,500 pg of modified BoNT / A, for example from 157,500 pg to 175,000 pg of modified BoNT / A, for example from 163,000 pg to 167,000 pg of modified BoNT / A. The total dose can be approximately 165,000 pg of modified BoNT / A.

[0152] The total dose can be up to 121,500 pg, 120,000 pg, 118,000 pg, 116,000 pg, 114,000 pg, 112,000 pg, or 110,000 pg of modified BoNT / A, for example, up to 110,000 pg of modified BoNT / A. The total dose can be about 110,000 pg (e.g., 110,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 110,000 pg of modified BoNT / A. The lower limit of the total dose range can be 60,000, 70,000, 80,000, or 90,000 pg of modified BoNT / A (preferably 60,000 pg of modified BoNT / A).

[0153] The total dose administered can be from 95,000 pg to 125,000 pg of modified BoNT / A; for example, from 102,500 pg to 117,500 pg of modified BoNT / A, or, for example, from 108,000 pg to 112,000 pg of modified BoNT / A. The total dose can also be approximately 110,000 pg of modified BoNT / A.

[0154] The total dose can be up to 60,500, 58,000, 56,000, or 55,000 pg of modified BoNT / A, for example, up to 55,000 pg of modified BoNT / A. The total dose can be about 55,000 pg (e.g., 55,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 55,000 pg of modified BoNT / A. The lower limit of the total dose range can be 45,000, 48,000, 51,000, 52,000, or 53,000 pg of modified BoNT / A (preferably 45,000 pg of modified BoNT / A).

[0155] The total dose can be from 40,000 pg to 67,500 pg of modified BoNT / A; for example, from 47,500 pg to 62,000 pg of modified BoNT / A, or from 53,000 pg to 57,000 pg of modified BoNT / A. The total dose can be about 60,000 pg of modified BoNT / A.

[0156] The total dose administered can be from 27,000 pg to 28,000 pg of modified BoNT / A. Therefore, 27,000 pg to 28,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). The total dose can also be about 27,500 pg (e.g., 27,500 pg ± 10%) of modified BoNT / A. Therefore, about 27,500 pg (e.g., 27,500 pg ± 10%) of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0157] The total dose administered can be from 31,000 pg to 33,000 pg of modified BoNT / A. Therefore, 31,000 pg to 33,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). The total dose can also be about 32,000 pg (e.g., 32,000 pg ± 10%) of modified BoNT / A. Therefore, about 32,000 pg (e.g., 32,000 pg ± 10%) of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0158] The total dose can be from 35,000 pg to 37,000 pg of modified BoNT / A. Therefore, 35,000 pg to 37,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). The total dose can also be about 36,000 pg (e.g., 36,000 pg ± 10%) of modified BoNT / A. Therefore, about 36,000 pg (e.g., 36,000 pg ± 10%) of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0159] The total dose can be 43,000 to 44,000 pg of modified BoNT / A. Therefore, 43,000 to 44,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein). The total dose can be about 44,000 pg (e.g., 44,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 44,000 pg of modified BoNT / A. Therefore, about 44,000 pg (e.g., 44,000 pg ± 10%) of modified BoNT / A can be administered to an individual, for example, 44,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0160] The total dose can be greater than 88,000 pg and at most 264,000 pg of modified BoNT / A. For example, the total dose administered when carrying out a treatment regimen can be greater than 88,000 pg and at most 240,000 pg of modified BoNT / A. Preferably, the total dose administered can be from 90,000 pg to 130,000 pg of modified BoNT / A; more preferably, the total dose administered can be from 100,000 pg to 120,000 pg of modified BoNT / A. A specific total dose when carrying out a treatment regimen can be 112,000 pg of modified BoNT / A.

[0161] The total dose administered during the treatment regimen can be from 230,000 pg to 264,000 pg of modified BoNT / A. Preferably, the total dose administered is from 235,000 pg to 250,000 pg of modified BoNT / A; more preferably, the total dose administered is from 239,000 pg to 241,000 pg of modified BoNT / A. A specific total dose administered during the treatment regimen can be 240,000 pg of modified BoNT / A.

[0162] The total dose administered during the treatment regimen can be from 150,000 pg to 176,000 pg of modified BoNT / A; preferably, the total dose administered is from 155,000 pg to 165,000 pg of modified BoNT / A; more preferably, the total dose administered is from 159,000 pg to 161,000 pg of modified BoNT / A. A particularly preferred total dose during the treatment regimen is 160,000 pg of modified BoNT / A.

[0163] The total dose administered during the treatment regimen can be from 70,000 pg to 88,000 pg of modified BoNT / A. Preferably, the total dose administered is from 75,000 pg to 85,000 pg of modified BoNT / A; more preferably, the total dose administered is from 79,000 pg to 81,000 pg of modified BoNT / A. The total dose can be 80,000 pg of modified BoNT / A.

[0164] The total dose administered during the treatment regimen can be 43,000 to 44,000 pg of modified BoNT / A. Therefore, an individual may be administered 43,000 to 44,000 pg of modified BoNT / A (e.g., via multiple unit doses as described herein). The total dose can be about 44,000 pg (e.g., 44,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 44,000 pg of modified BoNT / A. Therefore, an individual may be administered about 44,000 pg (e.g., 44,000 pg ± 10%) of modified BoNT / A, for example, an individual may be administered 44,000 pg of modified BoNT / A (e.g., via multiple unit doses as described herein).

[0165] The total dose administered when implementing a treatment regimen can be 60,000 to 70,000 pg of modified BoNT / A. Therefore, 60,000 to 70,000 pg of modified BoNT / A can be administered to an individual (e.g., through multiple unit doses as described herein). The total dose administered when implementing a treatment regimen can be 63,000 to 65,000 pg of modified BoNT / A. Therefore, 63,000 to 65,000 pg of modified BoNT / A can be administered to an individual (e.g., through multiple unit doses as described herein). The total dose can be about 64,000 pg (e.g., 64,000 pg ± 10%) of modified BoNT / A, for example, the total dose can be 64,000 pg of modified BoNT / A. Therefore, approximately 64,000 pg (e.g., 64,000 pg ± 10%) of modified BoNT / A can be administered to an individual, for example, 64,000 pg of modified BoNT / A can be administered to an individual (e.g., via multiple unit doses as described herein).

[0166] The total dose administered during the treatment regimen can be from 75,000 pg to 88,000 pg of modified BoNT / A. Therefore, 75,000 pg to 88,000 pg of modified BoNT / A can be administered to an individual (e.g., through multiple unit doses as described herein). The total dose can also be about 80,000 pg (e.g., 80,000 pg ± 10%) of modified BoNT / A. Therefore, about 80,000 pg (e.g., 80,000 pg ± 10%) of modified BoNT / A can be administered to an individual (e.g., through multiple unit doses as described herein).

[0167] When implementing the treatment regimen of the present invention, the total dose applied may be greater than 24,000 pg (e.g., preferably greater than 24,100 pg; more preferably greater than 35,000 pg; most preferably greater than 75,000 pg) of modified BoNT / A. In other words, the total amount of modified BoNT / A applied in a given treatment course may be greater than 24,000 pg. The total dose may be up to 82,500, 80,000, 75,000, 70,000, 65,000, 60,000, 55,000, 50,000, 45,000, 40,000, 35,000, 30,000, or 25,000 pg. The total dose can be at least 24,500, 25,000, 30,000, 35,000, 40,000, 45,000, 50,000, 55,000, 60,000, 65,000, or 70,000 pg. Preferably, the total dose can be at least 30,000 pg of modified BoNT / A. The total dose can be greater than 24,000 pg up to 70,000 pg, preferably from 30,000 pg to 60,000 pg.

[0168] The total dose can be greater than 35,000 pg to 70,000 pg.

[0169] The total dose can be 25,000 pg to 50,000 pg of modified BoNT / A (e.g., 25,000 pg to 50,000 pg). Examples of suitable total dose ranges include 25,000 pg to 35,000 pg of modified BoNT / A; and 45,000 pg to 50,000 pg of modified BoNT / A. Examples of suitable total doses include approximately 30,000 pg (e.g., 30,000 pg ± 10%) and approximately 48,000 pg (e.g., 48,000 pg ± 10%) of modified BoNT / A. This unit dosing regimen is particularly suitable for treating blepharospasm (whether bilateral or unilateral).

[0170] Therefore, the unit dose can be at least 240 pg of modified BoNT / A, and the total dose administered when implementing the treatment regimen of the present invention can be greater than 24,000 pg and at most 82,500 pg of modified BoNT / A. Alternatively, the unit dose can be at least 240 pg of modified BoNT / A, and the total dose administered when implementing the treatment regimen of the present invention can be greater than 35,000 pg and at most 82,500 pg of modified BoNT / A.

[0171] In a preferred embodiment, the unit dose may be at least 240 pg of modified BoNT / A, and the total dose administered when implementing the treatment regimen of the present invention may be greater than 24,000 pg and at most 75,000 pg of modified BoNT / A. Alternatively, the unit dose may be at least 240 pg of modified BoNT / A, and the total dose administered when implementing the treatment regimen of the present invention may be greater than 35,000 pg and at most 75,000 pg of modified BoNT / A.

[0172] In another preferred embodiment, the unit dose may be up to 5,000 pg of modified BoNT / A, and the total dose administered when implementing the treatment regimen of the present invention may be greater than 24,000 pg and up to 75,000 pg of modified BoNT / A. Alternatively, the unit dose may be up to 5,000 pg of modified BoNT / A, and the total dose administered when implementing the treatment regimen of the present invention may be greater than 35,000 pg and up to 75,000 pg of modified BoNT / A.

[0173] In cases of unilateral conditions (e.g., affecting one side of the face, such as unilateral blepharospasm of one eye), the total dose may refer to the total dose applied to the affected side of the face. In cases of bilateral conditions (e.g., affecting both sides of the face, such as unilateral blepharospasm of both eyes), the total dose may refer to the total dose applied to both sides of the face. Preferably, 50% of the total dose is applied to each side of the face (e.g., for bilateral blepharospasm, to each eye).

[0174] Preferably, the total dose administered may be 70,000 to 82,500 pg of modified BoNT / A, wherein each unit dose is 14,500 to 15,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be about 75,000 pg of modified BoNT / A, wherein each unit dose is about 15,000 pg of modified BoNT / A.

[0175] Preferably, the total dose administered during the treatment regimen may be 85,000 pg to 95,000 pg of modified BoNT / A, wherein each unit dose is 14,500 pg to 15,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be about 90,000 pg of modified BoNT / A, wherein each unit dose is about 15,000 pg of modified BoNT / A.

[0176] Preferably, the total dose administered during the treatment regimen may be from 140,000 pg to 165,000 pg of modified BoNT / A, wherein each unit dose is from 14,500 pg to 15,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be from about 150,000 pg of modified BoNT / A, wherein each unit dose is from about 15,000 pg of modified BoNT / A.

[0177] Preferably, the total dose administered during the treatment regimen may be from 155,000 pg to 177,500 pg of modified BoNT / A, wherein each unit dose is from 14,500 pg to 15,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be from about 165,000 pg of modified BoNT / A, wherein each unit dose is from about 15,000 pg of modified BoNT / A.

[0178] Preferably, the total dose administered during the treatment regimen may be 175,000 pg to 185,000 pg of modified BoNT / A, wherein each unit dose is 14,500 pg to 15,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be about 240,000 pg of modified BoNT / A, wherein each unit dose is about 15,000 pg of modified BoNT / A.

[0179] Preferably, the total dose administered during the treatment regimen may be from 225,000 pg to 260,000 pg of modified BoNT / A, wherein each unit dose is from 14,500 pg to 15,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be from about 240,000 pg of modified BoNT / A, wherein each unit dose is from about 15,000 pg of modified BoNT / A.

[0180] Preferably, the total dose administered during the treatment regimen may be 45,000 to 55,000 pg of modified BoNT / A, wherein each unit dose is 9,500 to 10,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be about 50,000 pg of modified BoNT / A, wherein each unit dose is about 10,000 pg of modified BoNT / A.

[0181] Preferably, the total dose administered during the treatment regimen may be 55,000 pg to 66,000 pg of modified BoNT / A, wherein each unit dose is 9,500 pg to 10,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen is about 60,000 pg of modified BoNT / A, wherein each unit dose is about 10,000 pg of modified BoNT / A.

[0182] Preferably, the total dose administered during the treatment regimen may be 90,000 pg to 110,000 pg of modified BoNT / A, wherein each unit dose is 9,500 pg to 10,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be about 100,000 pg of modified BoNT / A, wherein each unit dose is about 10,000 pg of modified BoNT / A.

[0183] Preferably, the total dose administered during the treatment regimen may be from 105,000 pg to 115,000 pg of modified BoNT / A, wherein each unit dose is from 9,500 pg to 10,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be from about 110,000 pg of modified BoNT / A, wherein each unit dose is from about 10,000 pg of modified BoNT / A.

[0184] Preferably, the total dose administered during the treatment regimen may be from 115,000 pg to 125,000 pg of modified BoNT / A, wherein each unit dose is from 9,500 pg to 10,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be from about 120,000 pg of modified BoNT / A, wherein each unit dose is from about 10,000 pg of modified BoNT / A.

[0185] Preferably, the total dose administered during the treatment regimen may be from 145,000 pg to 176,000 pg of modified BoNT / A, wherein each unit dose is from 9,500 pg to 10,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be from about 160,000 pg of modified BoNT / A, wherein each unit dose is from about 10,000 pg of modified BoNT / A.

[0186] Preferably, the total dose administered during the treatment regimen may be 83,000 pg to 90,000 pg of modified BoNT / A, wherein each unit dose is 6,500 pg to 7,500 pg of modified BoNT / A. More preferably, the total dose administered during the treatment regimen may be about 84,000 pg of modified BoNT / A, wherein each unit dose is about 7,000 pg of modified BoNT / A.

[0187] Preferably, the total dose administered during treatment may be 100,000 pg to 120,000 pg of modified BoNT / A, wherein each unit dose is 6,500 pg to 7,500 pg of modified BoNT / A. More preferably, the total dose administered during treatment may be about 112,000 pg of modified BoNT / A, wherein each unit dose is about 7,000 pg of modified BoNT / A.

[0188] In cases of unilateral conditions (e.g., affecting one side of the face, such as unilateral blepharospasm of one eye), the total dose may refer to the total dose applied to the affected side of the face. In cases of bilateral conditions (e.g., affecting both sides of the face, such as unilateral blepharospasm of both eyes), the total dose may refer to the total dose applied to both sides of the face. Preferably, 50% of the total dose is applied to each side of the face (e.g., for bilateral blepharospasm, to each eye).

[0189] Suitable disorders affecting eyelid muscles (e.g., affecting two or more eyelid muscles) include blepharospasm and facial spasm (e.g., unilateral facial spasm). Preferably, the disorder affecting individual eyelid muscles is blepharospasm. Therefore, the present invention can be used for the treatment of blepharospasm and / or facial spasm (e.g., unilateral facial spasm), preferably for the treatment of blepharospasm.

[0190] This invention builds upon the remarkable results of dose escalation studies demonstrating that these disorders can be treated with high doses of clostridium neurotoxin (e.g., greater than 24,000 pg and up to 82,500 pg) without exceeding acceptable levels of toxicity (see Examples), and is then supplemented by further clinical trial work outlined in Examples 11 and 22, which summarize the results of clinical trials in which unit and total doses of the modified BoNT / A (SEQ ID NO: 6, converted to double-stranded form) for facial injection were escalated, demonstrating that the molecule still has a favorable range for continued dose escalation while maintaining safety and efficacy. Notably, clinical evaluation of dose escalation data according to Example 22 showed that continued escalation of unit doses to 4,000 pg (total dose of 64,000 pg) was well tolerated and still below the maximum dose. Based on these findings, it is believed that higher unit doses can be administered to each muscle without adverse reactions. Furthermore, given that the toxin does not spread systemically, it is credible that up to 4-5 times the higher unit dose (Example 22) can be administered without safety concerns. For example, a unit dose of up to 10 ng or up to 15 ng would correspond to a total dose of up to 264,000 pg.

[0191] Disorders affecting an individual's eyelid muscles can be eyelid muscle disorders. The cause of the disorder can be a neurological disorder (e.g., VIIth neuropathy).

[0192] The modified BoNT / A can be applied to any muscle affected by the disorder (e.g., the affected eyelid muscles). The affected muscles may contribute to (e.g., cause) one or more symptoms of the disorder (e.g., blepharospasm and / or facial spasm, such as hemifacial spasm).

[0193] When performing the treatment of the present invention (preferably, when used to treat blepharospasm), a single unit dose of the modified BoNT / A is applied to at least the following groups: the lateral superior orbicularis oculi muscle near the individual's first eye (e.g., the lateral pre-tarsal orbicularis oculi muscle of the upper eyelid); the medial superior orbicularis oculi muscle near the individual's first eye (e.g., the medial pre-tarsal orbicularis oculi muscle of the upper eyelid); and the lateral inferior orbicularis oculi muscle near the individual's first eye (e.g., the lateral pre-tarsal orbicularis oculi muscle of the lower eyelid). Preferably, a single unit is applied to each injection site, which in this embodiment may correspond to application at three injection sites. Thus, three unit doses can be applied according to the method described above; however, other muscles and / or sites can be treated according to the present invention, meaning that the total number of unit doses applied may be greater than three.

[0194] When performing the treatment of the present invention (preferably, when used to treat blepharospasm), wherein the disorder affects the proximal eyelid muscles of both eyes (e.g., bilateral blepharospasm), a single unit dose of the modified BoNT / A is applied to at least the following groups: the lateral superior orbicularis oculi muscle near the first eye; the medial superior orbicularis oculi muscle near the first eye; the lateral inferior orbicularis oculi muscle near the first eye; the lateral superior orbicularis oculi muscle near the second eye; the medial superior orbicularis oculi muscle near the second eye; and the lateral inferior orbicularis oculi muscle near the second eye. Preferably, a single unit is applied to each injection site, which in this embodiment may correspond to application at six injection sites. Thus, six unit doses can be applied according to the above method; however, other muscles and / or sites can be treated according to the present invention, meaning that the total number of unit doses applied may be greater than six.

[0195] The terms "first eye" and "second eye" can refer to either the left or right eye. These terms are used only to distinguish the two eyes from each other. In other words, if the first eye is the left eye, then the second eye will be the right eye, and vice versa. Referring to the "first eye" does not always mean that the muscles and / or areas near the "second eye" need to be treated. For example, the "first eye" can be mentioned in the context of a unilateral disorder (such as unilateral blepharospasm), where the muscles and / or areas near the second eye are unaffected and therefore do not require treatment.

[0196] The term "proximal" refers to the muscle and / or part of the mentioned object that is closest to the eye. For example, if the first eye is an individual's left eye, then the muscle and / or part of the object closest to the first eye is the muscle and / or part of the object that is closer to the left eye than the individual's right eye.

[0197] The modified BoNT / A can be applied to one or more other muscles and / or sites thereof. When applied to other muscles and / or sites thereof, it is preferable to set an upper limit on the unit dose to ensure that the total amount of modified BoNT / A applied does not exceed the total dose to be applied during the treatment period as defined in this invention.

[0198] The other muscles and / or areas treated may be selected from one or more of the following (e.g., at least two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve, or all of the following muscles and / or areas): medial inferior orbicularis oculi, orbicularis oris (e.g., superior orbicularis oris and / or inferior orbicularis oris); zygomaticus major (e.g.); nasal muscles; mentalis; platysma; frontalis; corrugator supercilii; buccinator; masseter; depressor supercilii; and lateral canthus. The other muscles and / or areas treated may be selected from one or more of the following (e.g., at least two, three, four, five, six, seven, eight, nine, ten, eleven or twelve, or all of the following muscles and / or areas): medial inferior orbicularis oculi, superior orbicularis oris, inferior orbicularis oris, zygomaticus major, zygomaticus minor, frontalis, mentalis, platysma, corrugator supercilii, buccinator, masseter, depressor supercilii, nasalis, and levator palpebrae superioris. The other muscles and / or areas treated may be selected from one or more of the following (e.g., at least two, three, four, five, six, seven, eight, nine, ten, eleven or twelve, or all of the following muscles and / or areas): orbicularis oris superioris, orbicularis oris inferioris, zygomaticus major, zygomaticus minor, frontalis, mentalis, platysma, corrugator supercilii, buccinator, masseter, depressor supercilii, nasalis, and levator palpebrae superioris.

[0199] The muscles to which the treatment is applied according to the invention are listed, and the invention may also include the application of other muscles not listed.

[0200] Muscles and / or areas near one or both eyes may be treated as needed. At least a single unit dose may be applied to the muscles and / or areas, for example, two or more (e.g., three or more, four or more, or five or more) unit doses may be applied.

[0201] The modified BoNT / A can also be applied to the medial inferior orbicularis oculi muscle (e.g., the medial pre-tarsal orbicularis oculi muscle of the lower eyelid). In one embodiment, a single unit dose may be applied to the medial inferior orbicularis oculi muscle. The medial inferior orbicularis oculi muscle adjacent to one or both eyes may be treated as needed.

[0202] The modified BoNT / A can also be applied to the frontalis muscle. In one embodiment, at least a single unit dose may be applied to the frontalis muscle, for example, two or more, three or more, four or more, or five or more unit doses may be applied. The frontalis muscle near one or both eyes may be treated as needed.

[0203] Modified BoNT / A can also be applied to the corrugator supercilii muscle. In one embodiment, at least a single unit dose may be applied to the corrugator supercilii muscle, for example, two or more, three or more, four or more, or five or more unit doses may be applied. The corrugator supercilii muscle near one or both eyes may be treated as needed.

[0204] When treating facial spasms, one or more (e.g., at least two, three, four, five, six, seven, eight, nine, ten, or eleven or all) additional muscles and / or parts thereof may be treated, wherein the one or more muscles and / or parts thereof are selected from: the orbicularis oris muscle (e.g., the superior orbicularis oris and / or the inferior orbicularis oris); the zygomaticus major muscle (e.g., the zygomaticus major muscle); the nasal muscles; the mentalis muscle; the platysma muscle; the frontalis muscle; the corrugator supercilii muscle; the buccinator muscle; the masseter muscle; the depressor supercilii muscle; and the lateral canthus. When treating facial spasms, one or more (e.g., at least two, three, four, five, six, seven, eight, nine, ten, or eleven or all) additional muscles and / or parts thereof may be treated, wherein the one or more muscles and / or parts thereof are selected from: the orbicularis oris muscle (e.g., the superior orbicularis oris and / or the inferior orbicularis oris); the zygomaticus major muscle (e.g., the zygomaticus major and / or the zygomaticus minor); the nasal muscles; the mentalis muscle; the platysma muscle; the frontalis muscle; the corrugator supercilii muscle; the buccinator muscle; the masseter muscle; the depressor supercilii muscle; and the levator palpebrae superioris muscle.

[0205] Preferably, one or more (e.g., at least two, three, four or all) additional muscles and / or parts are selected from: the corrugator supercilii, frontalis, zygomaticus major, buccinator, and masseter.

[0206] In cases where facial spasm is bilateral, the modified BoNT / A can be applied to any muscles and / or areas on both sides of an individual's face. When the facial spasm is unilateral facial spasm, the modified BoNT / A can be applied to any muscles and / or areas on the affected side of an individual's face. At least a single unit dose can be applied to the muscles and / or areas, for example, two or more (e.g., three or more, four or more, or five or more) unit doses can be applied.

[0207] The frontalis muscle can be the venter frontalis muscle.

[0208] The corrugator supercilii muscle can be referred to as the corrugator supercilii muscle.

[0209] When treating blepharospasm according to the present invention, it is particularly preferred that the modified BoNT / A be administered via intramuscular injection to each of the following sites: a) Lateral superior orbicularis oculi muscle; b) The medial superior orbicularis oculi muscle; and c) Lateral orbicularis oculi muscle.

[0210] The three sites directly outlined in the above paragraphs can be referred to as the “minimum” sites in the treatment of blepharospasm.

[0211] When treating blepharospasm according to the present invention, it is particularly preferred that the modified BoNT / A be administered intramuscularly to each of the following muscles: a) The lateral superior orbicularis oculi muscle affected by the aforementioned blepharospasm; b) The medial superior orbicularis oculi muscle affected by the aforementioned blepharospasm; and c) The lateral inferior orbicularis oculi muscle affected by the aforementioned blepharospasm.

[0212] In other words, when treating blepharospasm according to the present invention, it is particularly preferred that the modified BoNT / A be administered intramuscularly to each of the following muscles: a) Each lateral superior orbicularis oculi muscle affected by the aforementioned blepharospasm; b) Each medial superior orbicularis oculi muscle affected by the aforementioned blepharospasm; and c) Each lateral inferior orbicularis oculi muscle affected by the aforementioned blepharospasm.

[0213] For example, when treating blepharospasm, the method is particularly preferred to include: a) Apply up to two units of modified BoNT / A to the lateral superior orbicularis oculi muscle near the individual's first eye; b) Apply a unit dose of modified BoNT / A to the medial superior orbicularis oculi muscle near the individual's first eye; and c) Apply a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle near the individual's first eye.

[0214] In other words, when treating blepharospasm, the method is particularly preferred to include: a) Apply up to two units of modified BoNT / A to each lateral superior orbicularis oculi muscle affected by the oculomotor spasm.

[0215] b) Apply a unit dose of modified BoNT / A to each medial superior orbicularis oculi muscle affected by the said blepharospasm; and c) Apply a unit dose of modified BoNT / A to each lateral inferior orbicularis oculi muscle affected by the blepharospasm.

[0216] For example, when treating blepharospasm, the method is particularly preferred to include: a) Two units of modified BoNT / A were applied to the lateral superior orbicularis oculi muscle near the individual's first eye; b) A single unit dose of modified BoNT / A was applied to the medial superior orbicularis oculi muscle near the individual's first eye; and c) A single unit dose of modified BoNT / A is applied to the lateral inferior orbicularis oculi muscle near the individual's first eye.

[0217] In other words, when treating blepharospasm, the method is particularly preferred to include: a) Two unit doses of modified BoNT / A were applied to each lateral superior orbicularis oculi muscle affected by the oculomotor spasm.

[0218] b) Apply a single unit dose of the modified BoNT / A to each medial superior orbicularis oculi muscle affected by the said blepharospasm; and c) Apply a single unit dose of modified BoNT / A to each lateral inferior orbicularis oculi muscle affected by the blepharospasm.

[0219] The "upper" orbicularis oculi muscle mentioned refers to the orbicularis oculi muscle of the upper eyelid. Similarly, the "lower" orbicularis oculi muscle mentioned refers to the orbicularis oculi muscle of the lower eyelid.

[0220] Those skilled in the art will understand that the term "medial" (e.g., in an anatomical context) refers to the midline of the body. Similarly, those skilled in the art will understand that the term "lateral" (e.g., in an anatomical context) refers to the midline of the body away from it. Therefore: - The "lateral" orbicularis oculi superior muscle refers to the portion of the orbicularis oculi muscle in the upper eyelid that is located away from the midline of the body (e.g., see...). Figure 8 Positions (1) and (2)); - The "medial" orbicularis oculi superior muscle refers to the portion of the orbicularis oculi muscle in the upper eyelid that is positioned towards the midline of the body (e.g., see...). Figure 8 Position (2)); - The "lateral" orbicularis oculi muscle of the lower eyelid refers to the portion of the orbicularis oculi muscle located away from the midline of the body (e.g., see...). Figure 8 Position (4)).

[0221] The term "lateral superior orbicularis oculi muscle" can be used synonymously with the term "external orbicularis oculi muscle of the upper eyelid." The term "medial superior orbicularis oculi muscle" can be used synonymously with the term "internal orbicularis oculi muscle of the upper eyelid." The term "lateral inferior orbicularis oculi muscle" can be used synonymously with the term "external orbicularis oculi muscle of the lower eyelid."

[0222] The orbicularis oculi muscle consists of the "pretarsal portion" and the "preseptal portion" (both of which can be injected).

[0223] Therefore, applying to the lateral superior orbicularis oculi may mean applying to the lateral "pretarsal" superior orbicularis oculi or applying to the lateral "preseptal" superior orbicularis oculi.

[0224] Applying to the medial superior orbicularis oculi muscle may mean applying to the medial superior "pre-tarsal" orbicularis oculi muscle, or applying to the medial superior "pre-orbital septum" orbicularis oculi muscle.

[0225] Applying to the lower lateral orbicularis oculi muscle may mean applying to the lower lateral "pretarsal" orbicularis oculi muscle, or applying to the lower lateral "preseptal" orbicularis oculi muscle.

[0226] When applied to the lateral superior orbicularis oculi muscle, the unit dose is preferably applied to the anterior portion of the orbital septum (in other words, applied to the lateral "anterior" superior orbicularis oculi muscle). When applied to the medial superior orbicularis oculi muscle, the unit dose is preferably applied to the anterior portion of the orbital septum (in other words, applied to the medial superior "anterior" superior orbicularis oculi muscle). When applied to the lateral inferior orbicularis oculi muscle, the unit dose is preferably applied to the anterior portion of the orbital septum (in other words, applied to the lateral inferior "anterior" superior orbicularis oculi muscle).

[0227] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two units (preferably one unit) to the corrugator supercilii muscle. (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle.

[0228] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; and / or (iii) Administer one unit dose to the depressor supercilii muscle.

[0229] In other words, when treating blepharospasm according to the present invention, the present invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) up to two unit doses (preferably one unit dose) per corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the blepharospasm); (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; and / or (iii) Administer one unit dose to the depressor supercilii muscle.

[0230] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) Administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; or administering one unit dose to the depressor supercilii muscle; and / or (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle.

[0231] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) At most two unit doses (preferably one unit dose) per corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the blepharospasm); or one unit dose is administered to the depressor supercilii muscle; and / or (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle.

[0232] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle, and / or administering one unit dose to the depressor supercilii muscle; and optionally (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle.

[0233] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) At most two unit doses (preferably one unit dose) are administered to each corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the blepharospasm), and / or one unit dose is administered to the depressor supercilii muscle; and optionally (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle.

[0234] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; and (iii) Administer one unit dose to the depressor supercilii muscle.

[0235] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) up to two unit doses (preferably one unit dose) per corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the blepharospasm); (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; and (iii) Administer one unit dose to the depressor supercilii muscle.

[0236] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) Administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; or administering one unit dose to the depressor supercilii muscle; and (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle.

[0237] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) At most two unit doses (preferably one unit dose) per corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the said blepharospasm); or one unit dose is administered to the depressor supercilii muscle; and (ii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle.

[0238] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) Administer one unit dose to the corrugator supercilii muscle; (ii) Administer two unit doses to the frontalis muscle (e.g., one unit dose per affected eye); and / or (iii) Administer one unit dose to the depressor supercilii muscle.

[0239] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) One unit dose per corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the blepharospasm); (ii) Administer two unit doses to the frontalis muscle (e.g., one unit dose per affected eye); and / or (iii) Administer one unit dose to the depressor supercilii muscle.

[0240] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) Administering one unit dose to the corrugator supercilii muscle, or one unit dose to the depressor supercilii muscle; and / or (ii) Administer two unit doses to the frontalis muscle (e.g., one unit dose per affected eye).

[0241] When treating blepharospasm according to the present invention, the invention may further include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) One unit dose per corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the said blepharospasm), or one unit dose administered to the depressor supercilii muscle; and / or (ii) Administer two units of the dose to the frontalis muscle.

[0242] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) Administer one unit dose to the corrugator supercilii muscle; (ii) Administer two unit doses to the frontalis muscle (e.g., one unit dose per affected eye); and (iii) Administer one unit dose to the depressor supercilii muscle.

[0243] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) One unit dose per corrugator supercilii muscle (e.g., the corrugator supercilii muscle affected by the blepharospasm); (ii) Administer two unit doses to the frontalis muscle (e.g., one unit dose per affected eye); and (iii) Administer one unit dose to the depressor supercilii muscle.

[0244] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) Administering one unit dose to the corrugator supercilii muscle, or one unit dose to the depressor supercilii muscle; and (ii) Administer two unit doses to the frontalis muscle (e.g., one unit dose per affected eye).

[0245] When treating blepharospasm according to the present invention, the invention may further include applying the modified BoNT / A to other muscles affected by said blepharospasm according to the following administration regimen: (i) One unit dose per corrugator supercilii muscle (e.g., the corrugator supercilii affected by the said blepharospasm), or one unit dose administered to the depressor supercilii muscle; and (ii) Administer two units of the dose to the frontalis muscle.

[0246] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the orbicularis oris muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0247] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the orbicularis oris muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by the blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0248] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the zygomaticus major muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the lower orbicularis oris muscle; (ii) Administer one unit dose to the upper orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0249] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the zygomaticus minor muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the orbicularis oris muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the frontalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0250] When treating blepharospasm according to the present invention, the invention may further include administering up to five unit doses (preferably one unit dose; more preferably two unit doses; most preferably three unit doses) to the frontalis muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve or more) other muscles affected by the blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer one unit dose to the orbicularis oris muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0251] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the mentalis muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the orbicularis oris muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0252] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the platysma muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the frontalis muscle; (vi) Administer one unit dose to the orbicularis oris muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0253] When treating blepharospasm according to the present invention, the invention may further include administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer one unit dose to the orbicularis oris muscle; (viii) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0254] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the buccinator muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) Administer one unit dose to the orbicularis oris muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xiii) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0255] When treating blepharospasm according to the present invention, the invention may further include administering up to two unit doses (preferably one unit dose) to the masseter muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) administer one unit dose to the orbicularis oris muscle; (ii) administer one unit dose to the zygomaticus major muscle; (iii) administer one unit dose to the zygomaticus minor muscle; (iv) administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) administer one unit dose to the mentalis muscle; (vi) administer one unit dose to the platysma muscle; (vii) administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) administer one unit dose to the buccinator muscle; (ix) administer one unit dose to the orbicularis oris muscle; (x) administer one unit dose to the depressor supercilii muscle; (xiii) administer one unit dose to the nasalis muscle; and / or (xii) administer one unit dose to the levator palpebrae superioris muscle.

[0256] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the depressor supercilii muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) administer one unit dose to the orbicularis oris muscle; (ii) administer one unit dose to the zygomaticus major muscle; (iii) administer one unit dose to the zygomaticus minor muscle; (iv) administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) administer one unit dose to the mentalis muscle; (vi) administer one unit dose to the platysma muscle; (vii) administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) administer one unit dose to the buccinator muscle; (ix) administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) administer one unit dose to the orbicularis oris muscle; (xv) administer one unit dose to the nasolabial muscle; and / or (xii) administer one unit dose to the levator palpebrae superioris muscle.

[0257] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the nasal muscles; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) administer one unit dose to the orbicularis oris muscle; (ii) administer one unit dose to the zygomaticus major muscle; (iii) administer one unit dose to the zygomaticus minor muscle; (iv) administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) administer one unit dose to the mentalis muscle; (vi) administer one unit dose to the platysma muscle; (vii) administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) administer one unit dose to the buccinator muscle; (ix) administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) administer one unit dose to the depressor supercilii muscle; (xiii) administer one unit dose to the orbicularis oris muscle; and / or (xii) administer one unit dose to the levator palpebrae superioris muscle.

[0258] When treating blepharospasm according to the present invention, the invention may further include administering a unit dose to the levator palpebrae superioris muscle; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said blepharospasm according to the following dosing regimen: (i) administer one unit dose to the orbicularis oris muscle; (ii) administer one unit dose to the zygomaticus major muscle; (iii) administer one unit dose to the zygomaticus minor muscle; (iv) administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) administer one unit dose to the mentalis muscle; (vi) administer one unit dose to the platysma muscle; (vii) administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (viii) administer one unit dose to the buccinator muscle; (ix) administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) administer one unit dose to the depressor supercilii muscle; (xiii) administer one unit dose to the nasalis muscle; and / or (xii) administer one unit dose to the orbicularis oris muscle.

[0259] As described above, in respect of the present invention for the treatment of typical hemifacial spasm, the present invention may include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said typical hemifacial spasm according to the following dosing regimens: (i) administering one unit dose to the superior orbicularis oris; (ii) administering one unit dose to the inferior orbicularis oris; (iii) administering one unit dose to the zygomaticus major muscle; (iv) administering one unit dose to the zygomaticus minor muscle; (v) administering up to five unit doses (preferably one unit dose) to the frontalis muscle; (vi) administering one unit dose to the mentalis muscle; (vii) administering one unit dose to the platysma muscle; (viii) administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) administering one unit dose to the buccinator muscle; (x) administering up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) administering one unit dose to the depressor supercilii muscle; (xii) administering one unit dose to the nasalis muscle; and / or (xiii) administering one unit dose to the levator palpebrae superioris muscle.

[0260] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: (i) administering a unit dose to the orbicularis oris muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasolabial muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle.

[0261] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include administering a unit dose to the orbicularis oris muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0262] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the zygomaticus major muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) the orbicularis oris muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0263] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the zygomaticus minor muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the orbicularis oris muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the frontalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0264] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering up to five unit doses (preferably one unit dose) to the frontalis muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer one unit dose to the orbicularis oris muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (iix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0265] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the mentalis muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the orbicularis oris muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0266] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the platysma muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the orbicularis oris muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasolabial muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0267] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer one unit dose to the orbicularis oris muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0268] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the buccinator muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the orbicularis oris muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0269] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering up to two unit doses (preferably one unit dose) to the masseter muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer one unit dose to the orbicularis oris muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0270] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the depressor supercilii muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the orbicularis oris muscle; (xi) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0271] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the nasal muscles affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the orbicularis oris muscle; and / or (xii) Administer one unit dose to the levator palpebrae superioris muscle.

[0272] In any aspect or embodiment of the invention for the treatment of typical hemifacial spasm, the invention may further include: administering a unit dose to the levator palpebrae superioris muscle affected by said typical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, or 12 or more) other muscles affected by said typical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the upper orbicularis oris muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer one unit dose to the zygomaticus minor muscle; (iv) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (v) Administer one unit dose to the mentalis muscle; (vi) Administer one unit dose to the platysma muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (ix) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (x) Administer one unit dose to the depressor supercilii muscle; (xi) Administer one unit dose to the nasalis muscle; and / or (xii) Administer one unit dose to the lower orbicularis oris muscle.

[0273] As described above, in respect of the present invention for the treatment of atypical hemifacial spasm, the present invention may include administering one or more unit doses of modified BoNT / A to one or more other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0274] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the zygomaticus major muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0275] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the zygomaticus minor muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0276] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering up to five unit doses (preferably one unit dose) to the frontalis muscle and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0277] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the mentalis muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the zygomaticus major muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0278] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the platysma muscle affected by the atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by the atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the zygomaticus major muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasolabial muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0279] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle affected by the atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by the atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the zygomaticus major muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0280] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the buccinator muscle affected by the atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by the atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the zygomaticus major muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0281] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering up to two unit doses (preferably one unit dose) to the masseter muscle affected by the atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by the atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer one unit dose to the zygomaticus major muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0282] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the depressor supercilii muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the zygomaticus major muscle; (x) Administer one unit dose to the nasolabial muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0283] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the nasal muscles affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the zygomaticus major muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0284] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the lateral superior orbicularis oculi muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the zygomaticus major muscle; (xii) Administer one unit dose to the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0285] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the medial superior orbicularis oculi muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasolabial muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose to the zygomaticus major muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0286] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the lateral inferior orbicularis oculi muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral orbicularis oculi muscle; (xii) Administer one unit dose to the medial orbicularis oculi muscle; (xiii) Administer one unit dose to the zygomaticus major muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle.

[0287] In any aspect or embodiment of the invention for the treatment of atypical hemifacial spasm, the invention may further include: (i) administering a unit dose to the levator palpebrae superioris muscle affected by said atypical hemifacial spasm; and optionally administering one or more unit doses of modified BoNT / A to one or more (e.g., 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, or 13 or more) other muscles affected by said atypical hemifacial spasm according to the following dosing regimen: (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five unit doses (preferably one unit dose) to the frontalis muscle; (iv) Administer one unit dose to the frontalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasalis muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose to the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the zygomaticus major muscle.

[0288] According to the present invention, the modified BoNT / A can be applied to muscles and / or their sites by any suitable method.

[0289] As an alternative to intramuscular injection, modified BoNT / A can be administered subcutaneously, for example by subcutaneous injection. The subcutaneous injection may, as needed, be injected medially and / or laterally into the junction between the anterior portion of the orbital septum of the superior and / or inferior orbicularis oculi muscles and the orbit.

[0290] Most preferably, the modified BoNT / A is administered intramuscularly, for example by intramuscular injection.

[0291] Electromyographic control / guidance can be used to assist in the application of the modified BoNT / A according to the present invention.

[0292] The term "unit dose" can include more than one unit dose. For example, the term "unit dose" can refer to up to two unit doses, up to three unit doses, up to four unit doses, or up to five unit doses. The term "unit dose" can also refer to a single unit dose.

[0293] A single unit dose can be administered to the affected muscle at one or more injection sites. When a single unit dose is administered at more than one injection site, the dose can be distributed (equally or unequally) among two or more injection sites. However, it is preferred to administer a single unit dose at each injection site.

[0294] The term "administer a single unit dose" means administering substantially the entire single unit dose. For example, a residual amount of the unit dose (e.g., at most 1%, 0.1%, or 0.01%) may remain in the vial in which the modified BoNT / A has been reconstructed. However, preferably, the entire single unit dose is administered (e.g., at one or more injection sites, preferably each injection site). This definition similarly applies to administering two unit doses, three unit doses, etc.

[0295] The term "at most" when used to refer to a value (e.g., at most 82,500 pg) means at most and includes the referenced value. Therefore, as an example, referring to a BoNT / A modified with "at most 82,500 pg" includes both BoNT / A modified with 82,500 pg and BoNT / A modified with less than 82,500 pg. As another example, referring to a BoNT / A modified with "at most 264,000 pg" includes both BoNT / A modified with 264,000 pg and BoNT / A modified with less than 264,000 pg.

[0296] The unit dose can be expressed as the amount of modified BoNT / A, the unit of modified BoNT / A, or a combination thereof.

[0297] The total number of unit doses applied can be up to 20, 15, 10, 5, or 3. The total number of unit doses applied can be at least 3, 5, 10, or 15. The total number of unit doses applied can be 3-20, 4-16, or 5-12. In one embodiment, 5 unit doses are applied. In one embodiment, 6 unit doses are applied. In one embodiment, 10 unit doses are applied. In one embodiment, 12 unit doses are applied. In one embodiment, 15 doses are applied. A total of 12 unit doses is preferred, particularly in the treatment of blepharospasm (more particularly bilateral blepharospasm).

[0298] The modified BoNT / A can be administered intramuscularly to a total of six, seven, eight, nine, ten, eleven, or twelve sites in an individual's first eye. The modified BoNT / A can also be administered intramuscularly to a total of six, seven, eight, nine, ten, or eleven sites in an individual's first eye. Alternatively, the modified BoNT / A can be administered intramuscularly to a total of six, seven, eight, nine, ten, eleven, or twelve sites in an individual's second eye. The modified BoNT / A can also be administered intramuscularly to a total of six, seven, eight, nine, ten, or eleven sites in an individual's second eye.

[0299] In a preferred embodiment, the modified BoNT / A is administered intramuscularly to a total of six sites in an individual's first eye. Alternatively, the modified BoNT / A may preferably be administered intramuscularly to a total of six sites in an individual's second eye.

[0300] In the treatment of blepharospasm (e.g., preferably bilateral blepharospasm), a dose of up to 12 units is preferably administered at the following sites: - Administer two unit doses to the lateral superior orbicularis oculi muscle of the affected ey...

Claims

1. A modified botulinum neurotoxin A (BoNT / A) for treating individual blepharospasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of the modified BoNT / A to up to six different injection sites near the orbicularis oculi muscle of the first eye of the individual, wherein the up to six different injection sites are selected from: i) Medial superior orbicularis oculi muscle; ii) Orbicularis oculi muscle of the superior orbit; iii) Lateral superior orbicularis oculi muscle; iv) Orbicularis oculi muscle of the outer orbit; v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and vi) the orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or b) Administering a unit dose of the modified BoNT / A to at least two different injection sites near the inferior orbicularis oculi muscle of the individual's first eye, wherein the at most two different injection sites are selected from: i) The medial inferior orbicularis oculi muscle; and ii) Lateral inferior orbicularis oculi muscle; and / or c) Applying a unit dose of the modified BoNT / A to at least two different injection sites, each injection site being selected from: i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and ii) A portion of the protractor supercilii muscle near the first eye of the individual; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

2. A modified botulinum neurotoxin A (BoNT / A) for treating individual blepharospasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of the modified BoNT / A to up to six different injection sites near the orbicularis oculi muscle of the first eye of the individual, wherein the up to six different injection sites are selected from: i) Medial superior orbicularis oculi muscle; ii) Orbicularis oculi muscle of the superior orbit; iii) Lateral superior orbicularis oculi muscle; iv) Orbicularis oculi muscle of the outer orbit; v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and vi) the orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or b) Administering a unit dose of the modified BoNT / A to at least two different injection sites near the inferior orbicularis oculi muscle of the individual's first eye, wherein the at most two different injection sites are selected from: i) The medial inferior orbicularis oculi muscle; and ii) Lateral inferior orbicularis oculi muscle; and / or c) Applying a unit dose of the modified BoNT / A to at least two different injection sites, each injection site being selected from: i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and ii) A portion of the protractor supercilii muscle near the first eye of the individual; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg) of modified BoNT / A. The total dose administered during treatment is greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

3. The modified BoNT / A according to claim 1 or claim 2, wherein the modified BoNT / A is administered by intramuscular injection to at least six different sites on the face of the individual; preferably, wherein the modified BoNT / A is administered by intramuscular injection to at least six different sites on each eye of the individual.

4. The modified BoNT / A according to any one of the preceding claims, wherein the method of treating blepharospasm further comprises: (a) Applying a unit dose of the modified BoNT / A to up to six different injection sites near the orbicularis oculi muscle of the second eye of the individual, wherein the up to six different injection sites are selected from: (i) The orbicularis oculi muscle anterior to the medial superior orbital septum; (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbital septum anterior orbicularis oculi muscle; (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) Administering a unit dose of the modified BoNT / A to at least two different injection sites near the orbicularis oculi muscle of the second eye of the individual, wherein the at most two different injection sites are selected from: (i) the medial inferior orbicularis oculi muscle; and (ii) Lateral inferior orbicularis oculi muscle; and / or (c) Applying a unit dose of the modified BoNT / A to at least two different injection sites, each injection site being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's second eye; and (ii) A site on the depressor supercilii muscle near the second eye of the individual (e.g., preferably, the depressor supercilii muscle receives a single unit dose of the modified BoNT / A).

5. The modified BoNT / A according to claim 4, wherein the modified BoNT / A is administered by intramuscular injection to at least six different sites in each eye of the individual.

6. The modified BoNT / A according to any one of the preceding claims, wherein the method comprises: (a) A unit dose of the modified BoNT / A is administered to the anterior orbicularis oculi muscle of the superior orbital septum near the first eye of the individual; (b) Administering a unit dose of the modified BoNT / A to the anterior orbicularis oculi muscle of the superior orbital septum near the first eye of the individual; and (c) A unit dose of modified BoNT / A is applied to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the first eye of the individual.

7. A modified botulinum neurotoxin A (BoNT / A) for treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: (a) Applying a unit dose of the modified BoNT / A to up to six different injection sites near the orbicularis oculi muscle of the first eye of the individual, wherein the up to six different injection sites are selected from: (i) The orbicularis oculi muscle anterior to the medial superior orbital septum; (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbital septum anterior orbicularis oculi muscle; (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) Applying a unit dose of the modified BoNT / A to at least two different injection sites near the orbicularis oculi muscle of the first eye of the individual, wherein the at most two different injection sites are selected from: (i) the medial inferior orbicularis oculi muscle; and (ii) Lateral inferior orbicularis oculi muscle; and / or (c) Applying a unit dose of the modified BoNT / A to at least two different injection sites, each injection site being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A portion of the protractor supercilii muscle near the first eye of the individual; and / or (d) Administer one or more unit doses of modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

8. A modified botulinum neurotoxin A (BoNT / A) for treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: (a) Applying a unit dose of the modified BoNT / A to up to six different injection sites near the orbicularis oculi muscle of the first eye of the individual, wherein the up to six different injection sites are selected from: (i) The orbicularis oculi muscle anterior to the medial superior orbital septum; (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbital septum anterior orbicularis oculi muscle; (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or (b) Applying a unit dose of the modified BoNT / A to at least two different injection sites near the orbicularis oculi muscle of the first eye of the individual, wherein the at most two different injection sites are selected from: (i) the medial inferior orbicularis oculi muscle; and (ii) Lateral inferior orbicularis oculi muscle; and / or (c) Applying a unit dose of the modified BoNT / A to at least two different injection sites, each injection site being selected from: (i) Two different injection sites on the corrugator supercilii muscle near the individual's first eye; and (ii) A portion of the protractor supercilii muscle near the first eye of the individual; and / or (d) Administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg) of modified BoNT / A. The total dose administered during treatment is greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A includes a BoNT / A light chain and a translocation domain (HN) as well as a BoNT / B receptor-binding domain (HC domain).

9. The modified BoNT / A according to any one of the preceding claims, wherein the modified BoNT / A is administered by intramuscular injection to at least six different sites on the individual's face, preferably wherein the modified BoNT / A is administered by intramuscular injection to at least six different sites on each eye affected by the impairment.

10. The modified BoNT / A according to any one of the preceding claims, wherein the method comprises: (a) A unit dose of the modified BoNT / A is administered to the anterior orbicularis oculi muscle of the superior orbital septum near the first eye of the individual; (b) Administering a unit dose of the modified BoNT / A to the anterior orbicularis oculi muscle of the superior orbital septum near the first eye of the individual; and (c) A unit dose of modified BoNT / A is applied to the lateral inferior orbicularis oculi muscle (preferably the lateral inferior orbital septum anterior orbicularis oculi muscle) near the first eye of the individual.

11. A modified botulinum neurotoxin A (BoNT / A) for treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of the modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm); and b) Optionally, administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The orbicularis oculi muscle anterior to the medial superior orbital septum; (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbital septum anterior orbicularis oculi muscle; (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle; and (ii) Lateral inferior orbicularis oculi muscle; and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) An injection site for the depressor supercilii muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

12. A modified botulinum neurotoxin A (BoNT / A) for treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of the modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm); and b) Optionally, administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus minor muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer one unit dose to the buccinator muscle; (vii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (viii) Administer one unit dose to the nasal muscle; (ix) Administer one unit dose to the levator palpebrae superioris muscle; and / or c) Optionally, administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: At up to six different injection sites in the superior orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) The orbicularis oculi muscle anterior to the medial superior orbital septum; (ii) Orbicularis oculi muscle of the superior orbit; (iii) Lateral superior orbital septum anterior orbicularis oculi muscle; (iv) Orbicularis oculi muscle of the outer orbit; (v) The orbicularis oculi muscle anterior to the medial superior tarsal plate; and (vi) The orbicularis oculi muscle anterior to the lateral superior tarsal plate; and / or At up to two different injection sites in the lower orbicularis oculi muscle, a unit dose is injected at each injection site, wherein the injection sites are selected from: (i) the medial inferior orbicularis oculi muscle; and (ii) Lateral inferior orbicularis oculi muscle; and / or At most two different injection sites, each injection site is used to administer a unit dose, wherein the injection sites are selected from: (i) Two different injection sites for the corrugator supercilii muscle; and (ii) An injection site for the depressor supercilii muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg) of modified BoNT / A. The total dose administered during treatment is greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

13. A modified botulinum neurotoxin A (BoNT / A) for treating individual blepharospasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of the modified BoNT / A to the lateral superior orbicularis oculi muscle near the first eye of the individual; b) Apply a unit dose of the modified BoNT / A to the medial superior orbicularis oculi muscle near the first eye of the individual; as well as c) Apply a unit dose of the modified BoNT / A to the lateral inferior orbicularis oculi muscle near the first eye of the individual. The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

14. A modified botulinum neurotoxin A (BoNT / A) for treating individual blepharospasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of the modified BoNT / A to the lateral superior orbicularis oculi muscle near the first eye of the individual; b) Apply a unit dose of the modified BoNT / A to the medial superior orbicularis oculi muscle near the first eye of the individual; as well as c) Apply a unit dose of the modified BoNT / A to the lateral inferior orbicularis oculi muscle near the first eye of the individual. The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg) of modified BoNT / A. The total dose administered during treatment is greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

15. A modified botulinum neurotoxin A (BoNT / A) for treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of the modified BoNT / A to the lateral superior orbicularis oculi muscle of the eye near the eye affected by hemifacial spasm; b) Apply a unit dose of the modified BoNT / A to the medial superior orbicularis oculi muscle of the eye near the eye affected by hemifacial spasm; c) Apply a unit dose of the modified BoNT / A to the lateral inferior orbicularis oculi muscle of the eye near the eye affected by hemifacial spasm; as well as d) Administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg and at most 240,000 pg (e.g., at most 264,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

16. A modified botulinum neurotoxin A (BoNT / A) for treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Apply a unit dose of the modified BoNT / A to the lateral superior orbicularis oculi muscle of the eye near the eye affected by hemifacial spasm; b) Apply a unit dose of the modified BoNT / A to the medial superior orbicularis oculi muscle of the eye near the eye affected by hemifacial spasm; c) Apply a unit dose of the modified BoNT / A to the lateral inferior orbicularis oculi muscle of the eye near the eye affected by hemifacial spasm; as well as d) Administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg) of modified BoNT / A. The total dose administered during treatment is greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

17. A modified botulinum neurotoxin A (BoNT / A) for treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of the modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm); and b) Optionally, administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is greater than 8,000 pg of modified BoNT / A. The total dose administered during treatment is greater than 24,000 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a botulinum neurotoxin A (BoNT / A) light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

18. A modified botulinum neurotoxin A (BoNT / A) for treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection at multiple sites on the individual's face, the method comprising: a) Applying a unit dose of the modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and / or applying one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm; preferably applying one unit dose of the modified BoNT / A to the upper orbicularis oris muscle and one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm); and b) Optionally, administer one or more unit doses of the modified BoNT / A to one or more other muscles affected by the said hemifacial spasm according to the following dosing regimen: (i) Administer one unit dose to the zygomaticus major muscle; (ii) Administer one unit dose to the zygomaticus major muscle; (iii) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (iv) Administer one unit dose to the mentalis muscle; (v) Administer one unit dose to the platysma muscle; (vi) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (vii) Administer one unit dose to the buccinator muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (ix) Administer one unit dose to the depressor supercilii muscle; (x) Administer one unit dose to the nasal muscle; (xi) Administer one unit dose to the lateral superior orbicularis oculi muscle; (xii) Administer one unit dose into the medial superior orbicularis oculi muscle; (xiii) Administer one unit dose to the lateral inferior orbicularis oculi muscle; and / or (xiv) Administer one unit dose to the levator palpebrae superioris muscle; The unit dose of the modified BoNT / A is at least 240 pg (preferably at least 5500 pg) of modified BoNT / A. The total dose administered during treatment is greater than 82,500 pg and at most 264,000 pg (e.g., at most 240,000 pg) of the modified BoNT / A, and The modified BoNT / A comprises a BoNT / A light chain and a translocation domain (H). N ) and the BoNT / B receptor binding domain (H C (structural domain).

19. The modified BoNT / A according to any one of claims 1-6, 9-10, 13 or 14, further comprising administering one or more unit doses of the modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following dosing regimen: (i) Administer one unit dose to the orbicularis oris muscle; (ii) Administer one unit dose to the orbicularis oris muscle; (iii) Administer one unit dose to the zygomaticus major muscle; (iv) Administer one unit dose to the zygomaticus minor muscle; (v) Administer up to five units of the dose (preferably one unit) to the frontalis muscle; (vi) Administer one unit dose to the mentalis muscle; (vii) Administer one unit dose to the platysma muscle; (viii) Administer up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle; (ix) Administer one unit dose to the buccinator muscle; (x) Administer up to two unit doses (preferably one unit dose) to the masseter muscle; (xi) Administer one unit dose to the depressor supercilii muscle; (xii) Administer one unit dose to the nasal muscle; and / or (xiii) Administer one unit dose to the levator palpebrae superioris muscle.

20. The modified BoNT / A according to any one of claims 1-6, 9-10, 13-14 or 19, further comprising administering one or more unit doses of the modified BoNT / A to one or more other muscles affected by said blepharospasm according to the following administration regimen: (i) Administer one unit dose to the levator palpebrae superioris muscle.

21. The modified BoNT / A according to any one of the preceding claims, wherein the unit dose of the modified BoNT / A is greater than 8000 pg, and wherein the unit dose of the modified BoNT / A is at most 16,500 pg of modified BoNT / A.

22. The modified BoNT / A according to any one of the preceding claims, wherein the unit dose is greater than 8000 pg and at most 15,000 pg of modified BoNT / A.

23. The modified BoNT / A according to any one of the preceding claims, wherein the unit dose of the modified BoNT / A is greater than 8000 pg, and wherein the unit dose of the modified BoNT / A is at most 11,000 pg of modified BoNT / A.

24. The modified BoNT / A according to any one of the preceding claims, wherein the unit dose of the modified BoNT / A is greater than 8000 pg, and wherein the unit dose of the modified BoNT / A is at most 10,000 pg of modified BoNT / A.

25. The modified BoNT / A according to any one of claims 1-22, wherein the unit dose is 14,000 pg to 16,000 pg of modified BoNT / A, preferably wherein the unit dose is 14,500 pg to 15,500 pg of modified BoNT / A.

26. The modified BoNT / A according to any one of claims 1-22 or 25, wherein the unit dose is about 15,000 pg of modified BoNT / A, preferably wherein the unit dose is 15,000 pg of modified BoNT / A.

27. The modified BoNT / A according to any one of claims 1-23, wherein the unit dose is 9,000 pg to 11,000 pg of modified BoNT / A, preferably wherein the unit dose is 9,500 pg to 10,500 pg of modified BoNT / A.

28. The modified BoNT / A according to any one of claims 1-23 or 27, wherein the unit dose is about 10,000 pg of modified BoNT / A, preferably wherein the unit dose is 10,000 pg of modified BoNT / A.

29. The modified BoNT / A according to any one of claims 2-6, 8-10, 12, 14, 16 or 18, wherein the unit dose of the modified BoNT / A is 5500 pg to 8000 pg, preferably, wherein the unit dose of the modified BoNT / A is 6500 pg to 7500 pg of modified BoNT / A.

30. The modified BoNT / A according to any one of claims 2-6, 8-10, 12, 14, 16, 18 or 29, wherein the unit dose is about 7,000 pg of modified BoNT / A, preferably wherein the unit dose is 7,000 pg of modified BoNT / A.

31. The modified BoNT / A according to any one of the preceding claims, wherein the total dose of the modified BoNT / A administered during treatment is up to 240,000 pg.

32. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 264,000 pg.

33. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 248,000 pg; preferably The total dose of modified BoNT / A administered during treatment was between 210,000 pg and 235,000 pg; more preferably... The total dose of modified BoNT / A administered during treatment was approximately 225,000 pg.

34. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 225,000 pg.

35. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 198,000 pg; preferably The total dose of modified BoNT / A administered during treatment was between 170,000 pg and 190,000 pg; more preferably... The total dose of modified BoNT / A administered during treatment was 180,000 pg.

36. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 180,000 pg.

37. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 165,000 pg; preferably The total dose of modified BoNT / A administered during treatment was between 140,000 pg and 160,000 pg; more preferably... The total dose of modified BoNT / A administered during treatment was approximately 150,000 pg.

38. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 150,000 pg.

39. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 132,000 pg; preferably The total dose of modified BoNT / A administered during treatment was between 110,000 pg and 130,000 pg; more preferably... The total dose of modified BoNT / A administered during treatment was approximately 120,000 pg.

40. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 120,000 pg.

41. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 115,500 pg; preferably The total dose of modified BoNT / A administered during treatment is between 100,000 pg and 110,000 pg; more preferably... The total dose of modified BoNT / A administered during treatment was approximately 105,000 pg.

42. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 105,000 pg.

43. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 924,000 pg; preferably The total dose of modified BoNT / A administered during treatment is greater than 82,500 pg to 90,000 pg; more preferably... The total dose of modified BoNT / A administered during treatment was approximately 84,000 pg.

44. The modified BoNT / A according to any one of claims 1-31, wherein the total dose of the modified BoNT / A administered during treatment is greater than 82,500 pg to 84,000 pg.

45. The modified BoNT / A according to any one of the preceding claims, wherein the modified BoNT / A comprises a polypeptide sequence having at least 70% sequence identity with SEQ ID NO:

6.

46. ​​The modified BoNT / A according to any one of the preceding claims, wherein the safety ratio of the modified BoNT / A is greater than 7, wherein the safety ratio is calculated as: the toxin dose (measured in pg / mouse) required for a -10% change in body weight divided by DASED50 (measured in pg / mouse), wherein ED50 = the dose required to produce a DAS score of 2.

47. The modified BoNT / A according to any one of claims 1-6, 9-10, 13-14 or 19-46, wherein the method of treating blepharospasm further comprises: A unit dose of the modified BoNT / A was administered to the lateral superior orbicularis oculi muscle of the second eye closest to the individual; A unit dose of the modified BoNT / A was administered to the medial superior orbicularis oculi muscle of the second eye closest to the individual. and A unit dose of the modified BoNT / A was applied to the lateral inferior orbicularis oculi muscle of the second eye closest to the individual.

48. The modified BoNT / A according to any one of claims 1-6, 9-10, 13-14 or 19-47, wherein the method of treating blepharospasm further comprises applying: A unit dose of the modified BoNT / A is applied to the medial inferior orbicularis oculi muscle near the individual's eye, wherein the total dose of the modified BoNT / A applied during treatment does not exceed the dose described (e.g., in the preceding claims).

49. The modified BoNT / A according to any one of claims 1-6, 9-10, 13-14 or 19-48, wherein the method of treating blepharospasm further comprises applying: At least one unit dose (e.g., two unit doses) of the modified BoNT / A is applied to the frontalis muscle near the individual's eye, wherein the total dose of the modified BoNT / A applied during treatment does not exceed the dose described (e.g., in the preceding claim).

50. The modified BoNT / A according to any one of claims 1-6, 9-10, 13-14 or 19-49, wherein the method of treating blepharospasm further comprises applying: At least one unit dose (e.g., two unit doses) of the modified BoNT / A is applied to the corrugator supercilii muscle near the individual's eye, wherein the total dose of the modified BoNT / A applied during treatment does not exceed the dose described (e.g., in the preceding claim).

51. The modified BoNT / A according to any one of claims 1-6, 9-10, 13-14 or 19-50, wherein the method of treating blepharospasm further comprises applying: A unit dose of the modified BoNT / A is applied to the medial inferior orbicularis oculi muscle near the individual's eye, wherein the total dose of the modified BoNT / A applied during treatment does not exceed the dose described (e.g., in the preceding claims).

52. The modified BoNT / A according to any one of the preceding claims, wherein the modified BoNT / A is administered by a single unit dose at each injection site.

53. A modified BoNT / A unit dosage form, said unit dosage form comprising: a) BoNT / A modified with at least 240 pg (preferably 240 pg to 8000 pg; more preferably greater than 8000 pg; even more preferably 9500 pg to 15500 pg); and b) Optionally, pharmaceutically acceptable carriers, excipients, adjuvants, and / or salts. The modified BoNT / A comprises a BoNT / A light chain and a translocation domain, as well as a BoNT / B receptor-binding domain (H). C (structural domain).

54. A reagent kit comprising: a) The unit dosage form according to claim 53 (preferably, a plurality of said unit dosage forms); and b) The instructions for use in treating blepharospasm; and c) Optional, diluent.

55. A reagent kit comprising: (a) The unit dosage form according to claim 53 (preferably, a plurality of said unit dosage forms); and (b) Instructions for use in treating typical hemifacial spasm; and (c) Optionally, a diluent.

56. A reagent kit comprising: (a) The unit dosage form according to claim 53 (preferably, a plurality of said unit dosage forms); and (b) Instructions for use in the treatment of atypical hemifacial spasm; and (c) Optionally, a diluent.

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