Modified BoNT / A for use in treating disorders affecting the eyelid muscles of a subject - Patents.com

Abstract

The present invention relates to a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of the modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; and b) administering the unit dose of the modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject. and c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject, wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A, wherein the total dose administered during the treatment is up to 24000 pg of modified BoNT / A, and wherein the modified BoNT / A is a light chain and translocation domain (H) of BoNT / A. N ) and the receptor-binding domain of BoNT / B (H C The present invention relates to a modified BoNT / A comprising a

Description

[Technical Field]

[0001] The present invention relates to the treatment of disorders affecting the eyelid muscles in a subject. [Background technology]

[0002] Disorders that affect the eyelid muscles can adversely affect the lives of those who suffer from them. Among these disorders, blepharospasm and facial spasms (e.g., hemifacial spasm) are particularly unpleasant.

[0003] Blepharospasm is primarily characterized by abnormal contraction of the orbicularis oculi muscle. More specifically, blepharospasm may manifest as uncontrollable excessive blinking and spasms of one or both eyes, which are further characterized by uncontrollable eyelid closure for a longer duration than the typical blink reflex. Symptoms of blepharospasm may be recurrent, lasting for several hours or days at a time, and in some cases, the symptoms (e.g., spasms) may be chronic and persistent, causing lifelong difficulties for subjects suffering from this condition. Other symptoms may include spasms that can spread to the nose, face, and neck, dry eyes, and sensitivity to sunlight and bright light.

[0004] The cause of blepharospasm is not well understood.It has been suggested that blepharospasm can be triggered by certain drugs, such as those used to treat Parkinson's disease, estrogen replacement therapy, or acute withdrawal from benzodiazepines.Blepharospasm may also be associated with brain disorders (including, for example, neurodegenerative conditions, dysfunction of the basal ganglia of the brain, and multiple sclerosis), brain damage, or head trauma (for example, concussion).

[0005] Hemifacial spasm is a movement disorder characterized by involuntary tonic-clonic contractions of the facial muscles on one side of the face. Bilateral cases are occasionally observed, but these are extremely rare. The affected muscles are innervated by the facial nerve (cranial nerve VII). Initially, symptoms of this disorder are typically located in the orbicularis oculi muscle (e.g., typical hemifacial spasm) and can spread to include other facial muscles. Hemifacial spasm (HFS) takes two forms: typical HFS and atypical HFS. In the typical form, spasms / spasms typically begin in the orbicularis oculi muscle of the lower eyelid. Over time, this spreads to the entire eyelid, then the orbicularis oris muscle around the lip and the buccinator muscle in the zygomatic region. In atypical HFS, spasms / spasms typically begin in the orbicularis oris muscle around the lip and the buccinator muscle in the zygomatic region of the lower face, and then progress over time to the orbicularis oculi muscle in the eyelid. The most common form is the typical form, while the atypical form is seen in only about 2% to 3% of patients with hemifacial spasm.

[0006] Drug therapy for disorders affecting a subject's eyelid muscles has generally proven unpredictable and short-term. Anticholinergics, sedatives, and botulinum neurotoxin (e.g., Dysport®, Botox®, or Xeomin®) are the most commonly used treatment options. However, these treatment options are suboptimal and are associated with serious side effects, including toxicity and unwanted paralysis of facial muscles. In some cases, invasive surgical procedures may be considered for patients who do not respond adequately to drug therapy or botulinum neurotoxin injections. Therefore, new and effective therapies for treating blepharospasm are constantly being tested and sought.

[0007] More specifically, botulinum neurotoxin A (BoNT / A) selectively inhibits the release of acetylcholine from presynaptic nerve terminals, thereby blocking cholinergic transmission at the neuromuscular junction, causing muscle contraction and a decrease in muscle tone, resulting in relaxation of the injected muscle. However, currently available BoNT / A products have a duration of action of approximately 12 to 14 weeks, at which point new nerve terminals sprout, nerve function returns to normal, and the original symptoms recur. Therefore, injections must be repeated periodically to maintain efficacy. Thus, the frequency of BoNT / A injections is an important consideration for the treatment of disorders affecting a subject's eyelid muscles (e.g., blepharospasm and / or hemifacial spasm), given the potential for chronicity of the condition and the long-term nature of the required treatment. Indeed, this impacts the direct and indirect medical costs associated with patients and healthcare professionals, the cost of injections within the hospital / clinic, and, most importantly, the patient's quality of life.

[0008] Dysport® is approved for the treatment of blepharospasm and hemifacial spasm at a maximum total dose of 120 units per eye per treatment session. Clinicians are required to administer Dysport® to the subject's eyelid muscles up to an upper threshold of 120 units total per eye per treatment session (i.e., 240 units when treating both eyes). Clinicians are faced with difficult choices during patient treatment. In other words, in conventional treatment plans, clinicians must find a balance between a relatively low total amount of BoNT / A that can be administered (necessitated by the highly toxic nature of BoNT / A) and an effective dose in multiple different muscles and / or their regions. Thus, certain muscles may be neglected, while other muscles receive suboptimal amounts of BoNT / A, resulting in suboptimal therapy.

[0009] Furthermore, conventional treatment regimens for such disorders are complex, resulting in clinicians underdosing to avoid patient toxicity. Thus, there is a need for a convenient, safe, and effective single-dose unit, and corresponding guidance on the number of units (including, for example, the number of injection sites per muscle) that can be administered to the eyelid muscle during a treatment session without causing patient toxicity.

[0010] In summary, there is a need for improved treatments for disorders affecting a subject's eyelid muscles (e.g., blepharospasm and / or hemifacial spasm) that allow for a personalized, patient-centered approach to tailor treatment according to the targeted clinical pattern, allowing for injection into various combinations of muscles and / or sites depending on the distribution, extent, and severity of the disorder, while avoiding toxicity and providing longer-lasting treatment (resulting in less frequent administration).

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

[0012] The present inventors have surprisingly found that modified BoNT / A is particularly useful in treating disorders affecting the eyelid muscles of a subject (e.g., blepharospasm and / or hemifacial spasm). Modified BoNT / A comprises a light chain and translocation domain of BoNT / A and a receptor binding domain (H) of BoNT / B. C The modified BoNT / A may comprise a surface-exposed amino acid residue (e.g., a nucleotide sequence) and a surface-exposed amino acid residue (e.g., a nucleotide sequence) that results in a modified BoNT / A that exhibits increased retention at the site of administration (reduced diffusion from the site of administration) and / or a prolonged duration of action (e.g., 6 to 9 months). Alternatively, the modified BoNT / A may comprise one or more modifications of surface-exposed amino acid residues that result in an increased net positive charge. The increased charge promotes electrostatic interactions between the polypeptide and anionic extracellular components, thereby facilitating binding between the polypeptide and the cell surface. In turn, this also results in increased retention at the site of administration (reduced diffusion from the site of administration) and / or a prolonged duration of action (e.g., 6 to 9 months).

[0013] Advantageously, modified BoNT / A has an improved safety profile compared to unmodified BoNT / A (e.g., Dysport®). This improved safety profile can be expressed by the high safety margins described herein for modified BoNT / A.

[0014] Based on the preclinical data herein, it has been revealed that a higher total amount of modified BoNT / A can be administered to a subject while achieving a safety profile similar to that of unmodified BoNT / A (e.g., Dysport®) even at such high doses. Thus, in treating a disorder affecting a subject's eyelid muscles (e.g., blepharospasm and / or hemifacial spasm, such as typical hemifacial spasm), more modified BoNT / A can be injected and / or a greater number of muscles and / or sites can be injected before reaching a maximum total dose. This is a significant and advantageous finding, resulting in improved treatment of such disorders while providing clinicians with a wider range of treatment options. Treatment may be improved in that it provides longer-lasting treatment (resulting in less frequent administration), and / or the treatment can be tailored to the subject, and / or results in improved quality of life for the subject compared to treatment with unmodified BoNT / A (e.g., Dysport®). Thus, the treatment of the present invention is improved compared to conventional treatment regimens.

[0015] Furthermore, the present invention provides not only a simple, safe, and effective single unit dose, but also the total (maximum) dosage that can be safely administered in a single treatment.The present invention also provides a corresponding guide to the number of times that the unit dose can be administered into the muscle without causing toxicity to the patient (including, for example, the number of injection sites per muscle).Therefore, the treatment of a subject's eyelid muscle-affecting disorder (e.g., blepharospasm and / or hemifacial spasm) according to the present invention is much easier for clinicians to understand, helping to avoid under- and / or over-medication.Furthermore, compared with conventional treatments, the treatment according to the present invention is much more satisfactory for the patient because it is better adapted to the patient's needs. DETAILED DESCRIPTION OF THE INVENTION

[0016] In one aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting an eyelid muscle in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 240 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0017] Throughout this disclosure, the eye proximal to the injection site may be referred to as the eye affected by the lesion.

[0018] Throughout this disclosure, the term "lateral superior orbicularis oculi muscle" may refer to the "lateral pretarsal orbicularis oculi muscle of the upper eyelid." Similarly, the term "medial superior orbicularis oculi muscle" may refer to the "medial pretarsal orbicularis oculi muscle of the upper eyelid." Furthermore, the term "lateral inferior orbicularis oculi muscle" may refer to the "lateral pretarsal orbicularis oculi muscle of the lower eyelid."

[0019] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 240 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0020] The term "treating a disorder affecting the eyelid muscles in a subject" can mean that one or more symptoms of the disorder in the subject are alleviated.

[0021] The term "treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with unmodified BoNT / A" may mean that one or more symptoms of the disorder in a subject are alleviated for a longer period of time after administration of a modified BoNT / A of the present invention compared to administration of unmodified BoNT / A. The alleviation may be determined by comparison with a comparable control subject with comparable symptoms who is treated with unmodified BoNT / A. During a period in which the severity of one or more symptoms in the control subject is substantially the same (e.g., the same) as before unmodified BoNT / A treatment, a subject treated with a modified BoNT / A according to the present invention may show an improvement in one or more comparable symptoms of at least 5%, at least 10%, at least 25%, or at least 50% compared to the severity of the one or more symptoms before treatment with modified BoNT / A. The unmodified BoNT / A is preferably one in which SEQ ID NO: 2 is present in a dichain form.

[0022] In one aspect, the present invention provides a method of treating a disorder affecting the eyelid muscles in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 240 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0023] In a related aspect, the invention provides a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 240 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0024] In one aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles in a subject, comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 240 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain) and provides use.

[0025] In a related aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles of a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 240 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain) and provides use.

[0026] One aspect is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, said method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a BoNT / A light chain and translocation domain (H N ) and the receptor binding domain of BoNT / B (H C A modified BoNT / A is provided, comprising:

[0027] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a BoNT / A light chain and translocation domain (H N ) and the receptor binding domain of BoNT / B (H C A modified BoNT / A is provided, comprising:

[0028] In a related embodiment, the invention provides a method of treating blepharospasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a BoNT / A light chain and translocation domain (H N ) and the receptor binding domain of BoNT / B (H C and a domain).

[0029] In a related aspect, the invention provides a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a BoNT / A light chain and translocation domain (H N ) and the receptor binding domain of BoNT / B (H C and a domain).

[0030] In one aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a BoNT / A light chain and translocation domain (H N ) and the receptor binding domain of BoNT / B (H C domain) and provides use.

[0031] In one aspect, the present invention provides a method for treating blepharospasm in a subject using a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a BoNT / A light chain and translocation domain (H N ) and the receptor binding domain of BoNT / B (H C domain) and provides use.

[0032] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C A modified BoNT / A is provided, comprising:

[0033] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C A modified BoNT / A is provided, comprising:

[0034] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C and a domain).

[0035] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C and a domain).

[0036] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C domain) and provides use.

[0037] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C domain) and provides use.

[0038] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C A modified BoNT / A is provided, comprising:

[0039] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C A modified BoNT / A is provided, comprising:

[0040] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C and a domain).

[0041] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C and a domain).

[0042] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C domain) and provides use.

[0043] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject for a longer period than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A consisting of the light chain and translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C domain) and provides use.

[0044] The term "typical hemifacial spasm" may be used interchangeably with the term "hemifacial spasm" throughout this disclosure.

[0045] The unit dose may be at least 240.4 pg, at least 500 pg, at least 1000 pg, at least 2000 pg, at least 3000 pg, or at least 4000 pg, preferably at least 1000 pg, wherein the modified BoNT / A comprises a light chain and translocation domain of BoNT / A and a receptor binding domain (H) of BoNT / B. C domain).

[0046] In one embodiment, 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 of muscles and / or sites to which the modified BoNT / A is administered. For example, if the total dose administered during treatment is up to 24,000 pg of modified BoNT / A and the administration is limited to the lateral superior orbicularis oculi muscle proximal to the first eye of the subject, the medial superior orbicularis oculi muscle proximal to the first eye, and the lateral inferior orbicularis oculi muscle proximal to the first eye, the upper limit of the unit dose can be 8,000 pg. If additional administration is performed to the lateral superior orbicularis oculi muscle proximal to the second eye of the subject, the medial superior orbicularis oculi muscle proximal to the second eye, and the lateral inferior orbicularis oculi muscle proximal to the second eye, the upper limit can be 4,000 pg (e.g., an upper limit of 4,000 pg per eye).

[0047] The unit dose may be 240 pg to 10,000 pg of modified BoNT / A, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C The unit dose may be 240 pg to 9500 pg of modified BoNT / A, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C The unit dose may be 240 pg to 9000 pg of modified BoNT / A, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C Preferably, the unit dose may be 240 pg to 8000 pg of modified BoNT / A, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. CThe upper limit of the unit dose range can be 7500 pg, 7000 pg, 6500 pg, 6000 pg, 5500 pg, 5000 pg, 4800 pg, 4500 pg, 4000 pg, 3500 pg, 3000 pg, 2500 pg, 2400 pg, 2000 pg, 1500 pg, or 1250 pg of modified BoNT / A. The lower limit of the unit dose range may be 300 pg, 400 pg, 500 pg, 600 pg, 700 pg, 800 pg, 900 pg, 1000 pg, 1500 pg, 2000 pg, 2500 pg, 3000 pg, 3500 pg, 4000 pg, 4500 pg, or 5000 pg of modified BoNT / A, preferably the lower limit is 1000 pg. The unit dose may be 1000 pg to 4800 pg, 1000 pg to 4000 pg, 1000 pg to 2400 pg, or 1000 pg to 2000 pg. The unit dose may be 240.4 pg, 500 pg, 1000 pg, 2000 pg, 3000 pg, 4000 pg, 5000 pg, 6000 pg, 7000 pg, or 8000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C The unit dose may be 240.4 pg, 500 pg, 1000 pg, 2000 pg, 3000 pg, or 4000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C Preferably, the unit dose may be 1000 pg, 2000 pg, 3000 pg, or 4000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C domain).

[0048] The total dose administered in practicing the treatment regimen of the present invention may be up to 24,000 pg of modified BoNT / A, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. Cdomain). In other words, the total amount of modified BoNT / A administered in a given treatment session may be up to 24,000 pg. The total dose may be up to 20,000 pg, up to 15,000 pg, up to 10,000 pg, up to 7,500 pg, or up to 6,000 pg. The total dose may be at least 720 pg, at least 800 pg, at least 900 pg, at least 1,000 pg, at least 2,000 pg, at least 3,000 pg, at least 4,000 pg, at least 5,000 pg, at least 7,500 pg, at least 10,000 pg, at least 12,500 pg, at least 15,000 pg, or at least 20,000 pg. Preferably, the total dose may be at least 3,000 pg of modified BoNT / A. The total dose may be between 720 pg and 24000 pg, preferably between 3000 pg and 24000 pg.

[0049] The total dose can be 720 pg, 800 pg, 900 pg, 1000 pg, 2000 pg, 3000 pg, 4000 pg, 5000 pg, 7500 pg, 10000 pg, 12500 pg, 15000 pg, or 20000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C For example, the total dose may be 6000 pg, 7500 pg, 10000 pg, 15000 pg, or 20000 pg, where the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C domain).

[0050] In one embodiment, the unit dose may be 1000 pg, and the total dose may be 6000 pg, 7500 pg, 10000 pg, 15000 pg, or 20000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. CIn one embodiment, the unit dose may be 2000 pg, and the total dose may be 6000 pg, 7500 pg, 10000 pg, 15000 pg, or 20000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C In one embodiment, the unit dose may be 3000 pg, and the total dose may be 6000 pg, 7500 pg, 10000 pg, 15000 pg, or 20000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C In one embodiment, the unit dose may be 4000 pg, and the total dose may be 6000 pg, 7500 pg, 10000 pg, 15000 pg, or 20000 pg, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C domain).

[0051] In one aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting an eyelid muscle in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0052] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0053] In one aspect, the present invention provides a method of treating a disorder affecting the eyelid muscles in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0054] In a related aspect, the invention provides a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0055] In one aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles in a subject, comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain) and provides use.

[0056] In a related aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles of a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B.C domain) and provides use.

[0057] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0058] In a related embodiment, the invention provides a method of treating blepharospasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0059] In a related aspect, the invention provides a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain). In one aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain) and provides use.

[0060] In one aspect, the present invention provides a method for treating blepharospasm in a subject using a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B.C domain) and provides use.

[0061] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0062] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0063] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0064] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0065] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain) and provides use.

[0066] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain) and provides use.

[0067] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. CA modified BoNT / A is provided, comprising:

[0068] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0069] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0070] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C and a domain).

[0071] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain) and provides use.

[0072] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject for a longer period than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 units (U) of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 998 U of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. Cdomain) and provides use.

[0073] The unit dose may be at least 21 U, at least 42 U, at least 83 U, at least 125 U, or at least 166 U, preferably at least 42 U, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain).

[0074] The unit dose may be 10 U to 332.7 U of modified BoNT / A, wherein the modified BoNT / A is a mixture of the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C The upper limit of the unit dose range can be 312U, 291U, 270U, ​​250U, 229U, 208U, 199.6U, 187U, 166.3U, 146U, 125U, 104U, 99.8U, 89.17U, 62U, or 52U of modified BoNT / A. The lower limit of the unit dose range can be 12U, 17U, 21U, 25U, 29U, 33U, 37U, 42U, 62U, 83U, 104U, 125U, 146U, 166U, 187U, or 208U of modified BoNT / A, preferably the lower limit is 42U. The unit dose may be 42U to 199.6U, 42U to 166.3U, 42U to 99.8U, or 42U to 83.17U.

[0075] The unit dose may be 10 units, 20.8 units, 41.6 units, 83.2 units, 124.8 units, 166.4 units, 207.8 units, 249.6 units, 291.2 units, or 332.8 units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C The unit dose may be 10 units, 20.8 units, 41.6 units, 83.2 units, 124.8 units, or 166.4 units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. CPreferably, the unit dose may be 41.6 units, 83.2 units, 124.8 units, or 166.4 units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C domain).

[0076] The total dose administered in practicing the treatment regimen of the present invention may be up to 998 U of modified BoNT / A, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain). In other words, the total amount of modified BoNT / A administered in a given treatment session can be up to 998 U. The total dose can be up to 832 U, up to 624 U, up to 416 U, up to 312 U, or up to 250 U. The total dose can be at least 30 U, at least 33 U, at least 37 U, at least 42 U, at least 83 U, at least 125 U, at least 166 U, at least 208 U, at least 312 U, at least 416 U, at least 520 U, at least 624 U, or at least 832 U. Preferably, the total dose can be at least 125 U of modified BoNT / A. The total dose can be between 30 U and 998 U, preferably between 125 U and 998 U.

[0077] The unit dose may be 29.9 Units, 33.3 Units, 37.4 Units, 41.6 Units, 83.2 Units, 124.8 Units, 166.4 Units, 208 Units, 312 Units, 416 Units, 520 Units, 624 Units, or 831.9 Units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C For example, the total dose may be 249.6 Units, 312 Units, 416 Units, 624 Units, or 831.9 Units, where the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H domain) of BoNT / B. C domain).

[0078] In one embodiment, the unit dose may be 41.6 units, and the total dose may be 249.6 units, 312 units, 416 units, 624 units, or 831.9 units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain).

[0079] In one embodiment, the unit dose may be 83.2 units, and the total dose may be 249.6 units, 312 units, 416 units, 624 units, or 831.9 units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain).

[0080] In one embodiment, the unit dose may be 124.8 units, and the total dose may be 249.6 units, 312 units, 416 units, 624 units, or 831.9 units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain).

[0081] In one embodiment, the unit dose may be 166.4 units, and the total dose may be 249.6 units, 312 units, 416 units, 624 units, or 831.9 units, wherein the modified BoNT / A comprises the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C domain).

[0082] In one aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting an eyelid muscle in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0083] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 84 pg (preferably 84 pg to 666.7 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0084] In one aspect, the present invention provides a method of treating a disorder affecting the eyelid muscles in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0085] In a related aspect, the invention provides a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0086] In one aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles in a subject, comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0087] In a related aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles of a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0088] One aspect is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, said method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0089] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0090] In a related embodiment, the invention provides a method of treating blepharospasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0091] In a related aspect, the invention provides a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0092] In one aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0093] In one aspect, the present invention provides a method for treating blepharospasm in a subject using a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0094] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0095] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0096] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0097] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0098] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0099] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0100] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0101] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0102] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0103] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0104] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0105] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject for a longer period than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0106] The unit dose can be at least 84.4 pg, at least 100 pg, or at least 250 pg, wherein the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue.

[0107] The unit dose can be 84 pg to 666.7 pg of modified BoNT / A, wherein the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN and (v) a deletion of a surface-exposed acidic amino acid residue. The upper limit of the unit dose range can be 650 pg, 600 pg, 550 pg, 500 pg, 450 pg, 400 pg, 350 pg, 333.3 pg, 300 pg, 250 pg, 200 pg, 166.7 pg, 150 pg, or 100 pg of the modified BoNT / A. The lower end of the unit dose range may be 100 pg, 125 pg, 150 pg, 200 pg, 250 pg, 300 pg, 350 pg, 400 pg, 450 pg, 500 pg, 550 pg, 600 pg, or 650 pg of modified BoNT / A. The unit dose may be between 100 pg and 400 pg, between 100 pg and 333.3 pg, between 100 pg and 200 pg, or between 100 pg and 166.7 pg.

[0108] The unit dose can be greater than 300 pg or greater than 500 pg of modified BoNT / A, where the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, where the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue. For example, the unit dose can be greater than 300 pg and up to 666.7 pg of modified BoNT / A, e.g., greater than 500 pg and up to 666.7 pg of modified BoNT / A.

[0109] The total dose administered in practicing the treatment regimens of the present invention may be up to 2000 pg of modified BoNT / A, wherein the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN The modified BoNT / A may comprise a modification at one or more amino acid residues selected from GLN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue. In other words, the total amount of modified BoNT / A administered in a given treatment session may be up to 2000 pg. The total dose may be up to 1750 pg, up to 1500 pg, up to 1000 pg, up to 750 pg, up to 500 pg, or up to 300 pg, preferably up to 1500 pg. The total dose may be at least 252 pg, at least 300 pg, at least 350 pg, at least 400 pg, at least 500 pg, at least 600 pg, at least 700 pg, at least 800 pg, at least 900 pg, at least 1000 pg, or at least 1250 pg. The total dose may be between 252 pg and 2000 pg, preferably between 300 pg and 1500 pg.

[0110] The total dose can be greater than 500 pg, or greater than 750 pg, or greater than 1000 pg of modified BoNT / A, where the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GL and (v) a deletion of a surface-exposed acidic amino acid residue.

[0111] The total dose can be greater than 500 pg and up to 2000 pg of modified BoNT / A, wherein the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN The modified BoNT / A may comprise a modification at one or more amino acid residues selected from GLN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue. For example, the total dose can be greater than 750 pg (preferably greater than 1000 pg) and up to 2000 pg of the modified BoNT / A.

[0112] In one aspect, the present invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting an eyelid muscle in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0113] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0114] In a related aspect, the present invention provides a method of treating a disorder affecting an eyelid muscle in a subject, said method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0115] In a related aspect, the invention provides a method of treating a disorder affecting the eyelid muscles in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), the method comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0116] In another related aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles in a subject, comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0117] In a related aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating a disorder affecting the eyelid muscles of a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to a first eye of the subject; administering a single unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to a first eye of the subject; wherein the single unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0118] One aspect is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, said method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0119] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0120] In a related embodiment, the invention provides a method of treating blepharospasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0121] In a related aspect, the invention provides a method of treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0122] In one aspect, the present invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0123] In one aspect, the present invention provides a method for treating blepharospasm in a subject using a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating blepharospasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0124] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0125] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0126] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0127] In a related embodiment, the invention provides a method of treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0128] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0129] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating typical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0130] Another embodiment is a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of a subject, said method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0131] In a related aspect, the invention provides a modified botulinum neurotoxin A (BoNT / A) for use in a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0132] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject, wherein a modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0133] In a related embodiment, the invention provides a method of treating atypical hemifacial spasm in a subject for a longer period of time than treatment with unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, the method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The method is selected from the following:

[0134] In one aspect, the present invention provides a use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject, wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0135] In one aspect, the invention provides the use of a modified botulinum neurotoxin A (BoNT / A) in the manufacture of a medicament for treating atypical hemifacial spasm in a subject for a longer period than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by said hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus major muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 10 U of modified BoNT / A, where 1 unit is the calculated median lethal dose in mice (LD 50 ) is the amount of modified BoNT / A equivalent to wherein the total dose administered during treatment is up to 237 U of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a use selected from the following:

[0136] The unit dose may be at least 12 U or at least 30 U, wherein the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue.

[0137] The unit dose can be 10 U to 79 U of modified BoNT / A, where the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN and (v) a deletion of a surface-exposed acidic amino acid residue. The upper end of the unit dose range can be 77 U, 71 U, 65 U, 59 U, 53 U, 47.4 U, 41 U, 39.5 U, 36 U, 30 U, 23.7 U, 19.75 U, 18 U, or 12 U of the modified BoNT / A. The lower end of the unit dose range may be 12 U, 15 U, 18 U, 24 U, 30 U, 36 U, 41 U, 47 U, 53 U, 59 U, 65 U, 71 U, or 77 U of modified BoNT / A. The unit dose may be 12 U to 47.4 U, 12 U to 39.5 U, 12 U to 23.7 U, or 12 U to 19.75 U.

[0138] The unit dose can be greater than 35.5 units or greater than 59.2 units of modified BoNT / A, where the modified BoNT / A is ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, where the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue. For example, the unit dose can be greater than 35.5 units and up to 80 units of the modified BoNT / A, e.g., greater than 59.2 units and up to 80 units of the modified BoNT / A.

[0139] The total dose administered in practicing the treatment regimens of the present invention can be up to 237 U of modified BoNT / A, where the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1217, GLN 1219, GLN 1220, GLN 1221, GLN 1222, GLN 1223, GLN 1224, GLN 1225, GLN 1226, GLN 1227, GLN 1228, GLN 1229, GLN 1230, GLN 1231, GLN 1232, GLN 1233, GLN 1234, GLN 1235, GLN 1236, GLN 1237, GLN 1238, GLN 1239, GLN 1240, GLN 1241, GLN 1242, GLN 1243, GLN 1244, GLN 1245 The modified BoNT / A may comprise a modification at one or more amino acid residues selected from ASN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue. In other words, the total amount of modified BoNT / A administered in a given treatment session may be up to 237 U. The total dose may be up to 207 U, up to 178 U, up to 118 U, up to 89 U, up to 59 U, or up to 36 U, preferably up to 178 U. The total dose may be at least 30 U, at least 36 U, at least 41 U, at least 47 U, at least 59 U, at least 71 U, at least 83 U, at least 95 U, at least 107 U, at least 118 U, or at least 148 U. The total dose may be between 30 U and 237 U, preferably between 36 U and 178 U.

[0140] The total dose can be greater than 59.2 units, or greater than 88.9 units, or greater than 118.5 units of modified BoNT / A, where the modified BoNT / A is ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GL and (v) a deletion of a surface-exposed acidic amino acid residue.

[0141] The total dose can be greater than 59.2 units and up to 236.9 units of modified BoNT / A, wherein the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN The modified BoNT / A may comprise a modification at one or more amino acid residues selected from GLN 1216, GLN 1229, ASN 1242, ASN 1243, SER 1274, and THR 1277, wherein the modification is selected from (i) substitution of a surface-exposed acidic amino acid residue with a basic amino acid residue, (ii) substitution of a surface-exposed acidic amino acid residue with an uncharged amino acid residue, (iii) substitution of a surface-exposed uncharged amino acid residue with a basic amino acid residue, (iv) insertion of a basic amino acid residue, and (v) deletion of a surface-exposed acidic amino acid residue. For example, the total dose can be greater than 88.9 units (preferably greater than 118.5 units) and up to 236.9 units of the modified BoNT / A.

[0142] Any disorder affecting the eyelid muscles of a subject (e.g., affecting two or more eyelid muscles) can be treated according to the present invention. Suitable disorders include blepharospasm and facial spasm (e.g., hemifacial spasm). Preferably, the disorder affecting the eyelid muscles of a subject is blepharospasm. Thus, the present invention can be directed to the treatment of blepharospasm and / or facial spasm (e.g., hemifacial spasm), and preferably to the treatment of blepharospasm.

[0143] A disorder affecting the eyelid muscles (e.g., affecting more than one eyelid muscle) can be hemifacial spasm. The hemifacial spasm can be typical hemifacial spasm or atypical hemifacial spasm (preferably typical hemifacial spasm).

[0144] The disorder affecting the eyelid muscles of the subject can be an eyelid muscle disorder. The cause of the disorder can be a nerve-related disorder (e.g., a VIIth neuropathy).

[0145] The modified BoNT / A can be administered to any muscle affected by the disorder (e.g., an affected eyelid muscle), which can contribute to (e.g., cause) one or more symptoms of the disorder (e.g., blepharospasm and / or facial spasms, such as hemifacial spasm).

[0146] In one embodiment, only a single unit dose of modified BoNT / A is administered to at least each of the following muscles: the lateral superior orbicularis oculi muscle proximal to the first eye of the subject (e.g., the lateral pretarsal orbicularis oculi muscle of the upper eyelid), the medial superior orbicularis oculi muscle proximal to the first eye of the subject (e.g., the medial pretarsal orbicularis oculi muscle of the upper eyelid), and the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject (e.g., the lateral pretarsal orbicularis oculi muscle of the lower eyelid). Preferably, a single unit is administered per injection site, which in this embodiment may correspond to administration at three injection sites. Thus, although three unit doses can be administered as described above, additional muscles and / or sites can be treated according to the present invention, meaning that the total number of unit doses administered may exceed three.

[0147] In one embodiment, when the disorder affects the eyelid muscles near both eyes of a subject (e.g., bilateral blepharospasm), only a single unit dose of modified BoNT / A can be administered to at least the lateral superior orbicularis oculi muscle near the first eye of the subject, the medial superior orbicularis oculi muscle near the first eye of the subject, the lateral inferior orbicularis oculi muscle near the first eye of the subject, the lateral superior orbicularis oculi muscle near the second eye of the subject, the medial superior orbicularis oculi muscle near the second eye of the subject, and the lateral inferior orbicularis oculi muscle near the second eye of the subject.Preferably, a single unit is administered per injection site, which in this embodiment can correspond to administration at six injection sites.Thus, although six unit doses can be administered as described above, additional muscles and / or sites can be treated according to the present invention, which means that the total number of unit doses administered can exceed six.

[0148] In aspects and embodiments directed to the treatment of blepharospasm, the total number of unit doses administered is preferably 3 or less (preferably 3), e.g., when the modified BoNT / A is administered to a muscle(s) proximal to only one eye, e.g., to at least each of the lateral superior orbicularis oculi muscle proximal to the subject's first eye, the medial superior orbicularis oculi muscle proximal to the subject's first eye, and the lateral inferior orbicularis oculi muscle proximal to the subject's first eye. However, the total number of unit doses can be 6 or less (preferably 6), e.g., when the modified BoNT / A is administered to a muscle(s) proximal to both eyes. For example, there may be a total of 3 unit doses or less (preferably 3 unit doses) per eye, so that a total of 6 unit doses or less (preferably 6 unit doses) can be administered to the subject, for example, the modified BoNT / A can be administered to at least each of the lateral superior orbicularis oculi muscle proximal to the subject's first eye, the medial superior orbicularis oculi muscle proximal to the subject's first eye, the lateral inferior orbicularis oculi muscle proximal to the subject's first eye, the lateral superior orbicularis oculi muscle proximal to the subject's second eye, the medial superior orbicularis oculi muscle proximal to the subject's second eye, and the lateral inferior orbicularis oculi muscle proximal to the subject's second eye.

[0149] However, the total number of unit doses administered can also be 15 or less (e.g., 15). For example, in addition to the muscles mentioned above, injection sites can be extended to the procerus (e.g., 1 unit dose administered to the procerus), frontalis (e.g., up to 4 unit doses to the frontalis), and / or corrugator supercilii (e.g., up to 4 unit doses to the corrugator supercilii, preferably 2 unit doses per corrugator supercilii).

[0150] The terms "first eye" and "second eye" can refer to either the left eye or the right eye. The terms simply serve to distinguish the two eyes from one another. In other words, if the first eye is the left eye, the second eye is the right eye, and vice versa. Reference to the "first eye" is not intended to imply that muscles and / or areas proximal to the "second eye" always need to be treated. For example, the "first eye" may be referred to in connection with a unilateral disorder, such as unilateral blepharospasm, where muscles and / or areas proximal to the second eye are not affected and therefore not treated.

[0151] The term "proximal" means that the muscle and / or region thereof is closest to the designated eye. For example, if the first eye is the left eye of a subject, then the muscle and / or region thereof proximal to the first eye is the muscle and / or region thereof closer to the left eye than to the right eye of the subject.

[0152] The modified BoNT / A can be administered to one or more additional muscles and / or sites. When administered to additional muscles and / or sites, an upper unit dose limit is preferably set to ensure that the total amount of modified BoNT / A administered does not exceed the total dose administered during treatment as defined in accordance with the present invention.

[0153] The additional muscles and / or regions to be treated can be one or more (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve, or all muscles and / or regions) selected from the medial inferior orbicularis oculi, orbicularis oris (e.g., superior orbicularis oris and / or inferior orbicularis oris), zygomaticus (e.g., zygomaticus major), nasal muscles, mentalis, platysma, frontalis, corrugator supercilii, buccinator, masseter, procerus, and lateral canthus. The additional muscles and / or regions to be treated can be one or more (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve, or all muscles and / or regions) selected from the medial inferior orbicularis oculi, superior orbicularis oris, inferior orbicularis oris, zygomaticus major, zygomaticus minor, frontalis, mentalis, platysma, corrugator supercilii, buccinator, masseter, procerus, nasalis, and levator palpebrae superioris. The additional muscles and / or regions to be treated can be one or more (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve, or all muscles and / or regions) selected from the superior orbicularis oris, inferior orbicularis oris, zygomaticus major, zygomaticus minor, frontalis, mentalis, platysma, corrugator supercilii, buccinator, masseter, procerus, nasal muscles, and levator palpebrae superioris.

[0154] If desired, muscles and / or areas proximal to one or both eyes can be treated. At least a single unit dose can be administered to the muscle and / or area, for example, two or more unit doses (e.g., three or more unit doses, four or more unit doses, or five or more unit doses).

[0155] The modified BoNT / A can also be administered to the medial inferior orbicularis oculi muscle (e.g., the medial pretarsal orbicularis oculi muscle of the lower eyelid). In one embodiment, only a single unit dose can be administered to the medial inferior orbicularis oculi muscle. If desired, the proximal medial inferior orbicularis oculi muscle of one or both eyes can be treated.

[0156] The modified BoNT / A can also be administered to the frontalis muscle. In one embodiment, at least a single unit dose can be administered to the frontalis muscle, for example, 2 or more unit doses, 3 or more unit doses, 4 or more unit doses, or 5 or more unit doses can be administered. If necessary, the frontalis muscle proximal to one or both eyes can be treated.

[0157] The modified BoNT / A can also be administered to the corrugator supercilii muscle. In one embodiment, at least a single unit dose can be administered to the corrugator supercilii muscle, for example, 2 or more unit doses, 3 or more unit doses, 4 or more unit doses, or 5 or more unit doses can be administered. If necessary, the corrugator supercilii muscle proximal to one or both eyes can be treated.

[0158] The modified BoNT / A can also be administered to the procerus muscle. In one embodiment, at least a single unit dose can be administered to the procerus muscle, for example, 2 or more unit doses, 3 or more unit doses, 4 or more unit doses, or 5 or more unit doses can be administered. Preferably, only a single unit dose can be administered to the procerus muscle.

[0159] The modified BoNT / A can also be administered to the levator muscle. In one embodiment, at least a single unit dose can be administered to the levator muscle, for example, 2 or more unit doses, 3 or more unit doses, 4 or more unit doses, or 5 or more unit doses can be administered. Preferably, only a single unit dose can be administered to the levator muscle. If necessary, the levator muscle proximal to one or both eyes can be treated.

[0160] When treating hemifacial spasm, one or more (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or at least eleven, or all) additional muscles and / or regions thereof can be treated, where the one or more muscles and / or regions thereof are selected from the orbicularis oris (e.g., superior orbicularis oris and / or inferior orbicularis oris), zygomaticus (e.g., zygomaticus major), nasal muscles, mentalis, platysma, frontalis, corrugator supercilii, buccinator, masseter, procerus, and lateral canthus. When treating hemifacial spasm, one or more (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or at least eleven, or all) additional muscles and / or regions thereof can be treated, where the one or more muscles and / or regions thereof are selected from the orbicularis oris (e.g., superior orbicularis oris and / or inferior orbicularis oris), zygomaticus (e.g., zygomaticus major and / or zygomaticus minor), nasal muscles, mentalis, platysma, frontalis, corrugator supercilii, buccinator, masseter, procerus, and levator palpebrae superioris muscles.

[0161] Preferably, one or more (e.g., at least two, at least three, or at least four, or all) additional muscles and / or sites are selected from the corrugator supercilii, frontalis, zygomaticus major, buccinator, and masseter muscles.

[0162] When the facial spasm is bilateral, the modified BoNT / A can be administered to any muscle and / or area on both sides of the subject's face. When the facial spasm is hemifacial spasm, the modified BoNT / A can be administered to any muscle and / or area on the affected side of the subject's face. At least a single unit dose can be administered to the muscle and / or area, for example, two or more unit doses (e.g., three or more unit doses, four or more unit doses, or five or more unit doses) can be administered.

[0163] The frontalis muscle may be a venter frontalis muscle.

[0164] The corrugator muscle may be a corrugator supercilii muscle.

[0165] The modified BoNT / A, in accordance with the present invention, can be administered to the muscle and / or site by any suitable means.

[0166] In one embodiment, the modified BoNT / A can be administered subcutaneously, for example, by subcutaneous injection, which can include injection medially and / or laterally into the junction between the preseptal part of the superior and / or inferior orbicularis oculi muscles and the orbital part, as appropriate.

[0167] In one embodiment, the modified BoNT / A can be administered intramuscularly, for example, by intramuscular injection. Most preferably, the modified BoNT / A is administered intramuscularly, for example, by intramuscular injection.

[0168] Electromyographic control / guidance can be used to assist in the administration of modified BoNT / A according to the present invention.

[0169] A single unit dose can be administered at one or more injection sites. If a single unit dose is administered at two or more injection sites, the unit dose can be divided (equally or unequally) between the two or more injection sites. However, it is preferred that a single unit dose be administered at each injection site.

[0170] In any aspect or embodiment of the invention described herein, the modified BoNT / A can be administered (preferably by intramuscular injection) to multiple sites on the subject's face.

[0171] In any aspect or embodiment of the invention directed to the treatment of blepharospasm, said aspect or embodiment preferably comprises: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of a subject; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject; wherein the unit dose and total dose of the modified BoNT / A are as specified in the above aspects or embodiments.

[0172] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said blepharospasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) One unit dose into the levator palpebrae superioris.

[0173] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose of modified BoNT / A to the superior orbicularis oris muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0174] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose of modified BoNT / A to the inferior orbicularis oris muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0175] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose of modified BoNT / A to the zygomaticus major muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the upper orbicularis oris muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0176] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose of modified BoNT / A to the zygomaticus minor muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the upper orbicularis oris muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0177] In any aspect or embodiment of the invention directed to the treatment of blepharospasm, the invention may further comprise administering up to 5 unit doses (preferably 1 unit dose, more preferably 2 unit doses, and most preferably 3 unit doses) of modified BoNT / A to the frontalis muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) 1 unit dose to the upper orbicularis oris muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0178] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose of modified BoNT / A to the mentalis muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the upper orbicularis oris muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0179] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose of modified BoNT / A to the platysma muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the upper orbicularis oris muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0180] In any aspect or embodiment of the invention directed to the treatment of blepharospasm, the invention may further comprise administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) 1 unit dose to the upper orbicularis oris muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0181] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose to the buccinator muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the upper orbicularis oris muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0182] In any aspect or embodiment of the invention directed to the treatment of blepharospasm, the invention may further comprise administering from 1 unit dose to up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, and optionally 1 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) 1 unit dose to the upper orbicularis oris muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0183] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose to the proximal muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the upper orbicularis oris muscle, (x) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0184] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose to the nasal bridge, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the upper orbicularis oris muscle, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0185] In any aspect or embodiment of the invention directed to treating blepharospasm, the invention may further comprise administering one unit dose to the levator palpebrae superioris muscle, and optionally 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) additional muscles affected by said blepharospasm, according to the following dosing regimen: (i) 1 unit dose to the lower orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (viii) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal bridge, and / or (xii) 1 unit dose to the upper orbicularis oris muscle.

[0186] In any aspect or embodiment of the invention directed to the treatment of blepharospasm, the invention may further comprise administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by the blepharospasm according to the following dosing regimen: (i) 1 unit dose to the levator palpebrae superioris muscle.

[0187] In any aspect or embodiment of the invention directed to the treatment of hemifacial spasm (preferably typical hemifacial spasm), said aspect or embodiment preferably comprises: a) administering a unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; d) administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose and total dose of the modified BoNT / A are as specified in the above aspects or embodiments.

[0188] As outlined above, in aspects of the invention directed to the treatment of typical hemifacial spasm, the invention may comprise administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimens: (i) 1 unit dose to the superior orbicularis oris muscle, (ii) 1 unit dose to the inferior orbicularis oris muscle, (iii) 1 unit dose to the zygomaticus major muscle, (iv) 1 unit dose to the zygomaticus minor muscle, (v) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (vi) 1 unit dose to the mentalis muscle, (vii) 1 unit dose to the platysma muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (ix) 1 unit dose to the buccinator muscle, (x) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (xi) 1 unit dose to the procerus muscle, (xii) 1 unit dose to the nasal muscle, and / or (xiii) 1 unit dose to the levator palpebrae superioris muscle.

[0189] In any aspect or embodiment of the invention directed to the treatment of typical hemifacial spasm, the invention may further comprise (i) administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (ii) 1 unit dose to the lower orbicularis oris muscle, (iii) 1 unit dose to the zygomaticus major muscle, (iv) 1 unit dose to the zygomaticus minor muscle, (v) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (vi) 1 unit dose to the mentalis muscle, (vii) 1 unit dose to the platysma muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (ix) 1 unit dose to the buccinator muscle, (x) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (xi) 1 unit dose to the procerus muscle, (xii) 1 unit dose to the nasal muscles, and / or (xiii) 1 unit dose to the levator palpebrae superioris muscle.

[0190] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the lower orbicularis oris muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0191] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the zygomaticus major muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus minor muscle, (iii) the lower orbicularis oris muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0192] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the zygomaticus minor muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the lower orbicularis oris muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0193] In any aspect or embodiment of the invention directed to the treatment of typical hemifacial spasm, the invention may further comprise administering up to 5 unit doses (preferably 1 unit dose) of modified BoNT / A to the frontalis muscle affected by said hemifacial spasm, and optionally 1 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) 1 unit dose to the lower orbicularis oris muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0194] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the mentalis muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the lower orbicularis oris muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0195] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the platysma muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the lower orbicularis oris muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0196] In any aspect or embodiment of the invention directed to the treatment of typical hemifacial spasm, the invention may further comprise administering up to two unit doses (preferably one unit dose) to the corrugator supercilii muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) 1 unit dose to the lower orbicularis oris muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0197] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the buccinator muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the lower orbicularis oris muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0198] In any aspect or embodiment of the invention directed to the treatment of typical hemifacial spasm, the invention may further comprise administering up to two unit doses (preferably one unit dose) of modified BoNT / A to the masseter muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) 1 unit dose to the lower orbicularis oris muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0199] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the procerus muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the lower orbicularis oris muscle, (xi) 1 unit dose to the nasal muscles, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0200] In any aspect or embodiment of the invention directed to treating typical hemifacial spasm, the invention may further comprise administering one unit dose of modified BoNT / A to the nasal muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the lower orbicularis oris muscle, and / or (xii) 1 unit dose to the levator palpebrae superioris muscle.

[0201] In any aspect or embodiment of the invention directed to the treatment of typical hemifacial spasm, the invention may further comprise administering one unit dose to the levator palpebrae superioris muscle affected by said hemifacial spasm, and optionally 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) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (i) 1 unit dose to the upper orbicularis oris muscle, (ii) 1 unit dose to the zygomaticus major muscle, (iii) 1 unit dose to the zygomaticus minor muscle, (iv) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (v) 1 unit dose to the mentalis muscle, (vi) 1 unit dose to the platysma muscle, (vii) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (iix) 1 unit dose to the buccinator muscle, (ix) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (x) 1 unit dose to the procerus muscle, (xi) 1 unit dose to the nasal bridge, and / or (xii) 1 unit dose to the lower orbicularis oris muscle.

[0202] If the disorder is atypical hemifacial spasm, the following administration steps may simply be optional: administering a single unit dose of modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the first eye of the subject; administering a single unit dose of modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; and Administering a single unit dose of the modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the first eye of the subject.

[0203] In any aspect or embodiment of the invention directed to the treatment of hemifacial spasm (preferably atypical hemifacial spasm), said aspect or embodiment preferably comprises: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by the hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus minor muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose and total dose of the modified BoNT / A are as specified in the above aspects or embodiments.

[0204] One aspect of the invention is a modified BoNT / A for use in a method of treating atypical hemifacial spasm, said method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by the hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus minor muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 24,000 pg of modified BoNT / A, and Here, the modified BoNT / A is a modified BoNT / A that contains the light chain and translocation domain of BoNT / A and the receptor binding domain (H) of BoNT / B. C A modified BoNT / A is provided, comprising:

[0205] Another aspect of the invention is a modified BoNT / A for use in a method of treating atypical hemifacial spasm, said method comprising: a) administering a unit dose of modified BoNT / A to the orbicularis oris muscle affected by the hemifacial spasm (e.g., administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm, preferably administering one unit dose of modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm); b) optionally administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus minor muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 84 pg (preferably 84 pg to 666.7 pg) of modified BoNT / A; wherein the total dose administered during treatment is up to 2000 pg of modified BoNT / A, and Here, the modified BoNT / A is selected from the group consisting of ASN 886, ASN 905, GLN 915, ASN 918, GLU 920, ASN 930, ASN 954, SER 955, GLN 991, GLU 992, GLN 995, ASN 1006, ASN 1025, ASN 1026, ASN 1032, ASN 1043, ASN 1046, ASN 1052, ASP 1058, HIS 1064, ASN 1080, GLU 1081, GLU 1083, ASP 1086, ASN 1188, ASP 1213, GLY 1215, ASN 1216, GLN 1229, ASN 1242, ASN 1243 ... 1274, and THR 1277, wherein the modification is at one or more amino acid residues selected from (i) substitution of surface-exposed acidic amino acid residues with basic amino acid residues; (ii) substitution of surface-exposed acidic amino acid residues with uncharged amino acid residues; (iii) substitution of surface-exposed uncharged amino acid residues with basic amino acid residues; (iv) insertion of a basic amino acid residue, and (v) deletion of surface-exposed acidic amino acid residues; The present invention provides a modified BoNT / A selected from the following:

[0206] The term "unit dose" can be used interchangeably with the term "single unit dose."

[0207] As outlined above, in aspects of the invention directed to the treatment of atypical hemifacial spasm, the invention may involve administering one or more unit doses of modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose to the zygomaticus major muscle, (ii) 1 unit dose to the zygomaticus minor muscle, (iii) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (iv) 1 unit dose to the mentalis muscle, (v) 1 unit dose to the platysma muscle, (vi) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (vii) 1 unit dose to the buccinator muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (ix) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, (xi) 1 unit dose to the lateral orbicularis oculi superior muscle, (xii) 1 unit dose to the medial orbicularis oculi superior muscle, (xiii) 1 unit dose to the lateral orbicularis oculi inferior muscle, and / or (xiv) 1 unit dose to the levator palpebrae superioris muscle.

[0208] In any aspect or embodiment of the invention directed to the treatment of atypical hemifacial spasm, the invention may further comprise (i) administering one unit dose of modified BoNT / A to the zygomaticus major muscle affected by said hemifacial spasm, and optionally 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, twelve or more, or thirteen or more) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (ii) 1 unit dose to the zygomaticus minor muscle, (iii) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (iv) 1 unit dose to the mentalis muscle, (v) 1 unit dose to the platysma muscle, (vi) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (vii) 1 unit dose to the buccinator muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (ix) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, (xi) 1 unit dose to the lateral orbicularis oculi superior muscle, (xii) 1 unit dose to the medial orbicularis oculi superior muscle, (xiii) 1 unit dose to the lateral orbicularis oculi inferior muscle, and / or (xiv) 1 unit dose to the levator palpebrae superioris muscle.

[0209] In any aspect or embodiment of the invention directed to the treatment of atypical hemifacial spasm, the invention may further comprise (i) administering one unit dose of modified BoNT / A to the zygomaticus minor muscle affected by said hemifacial spasm, and optionally 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, twelve or more, or thirteen or more) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (ii) 1 unit dose to the zygomaticus major muscle, (iii) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (iv) 1 unit dose to the mentalis muscle, (v) 1 unit dose to the platysma muscle, (vi) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (vii) 1 unit dose to the buccinator muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (ix) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, (xi) 1 unit dose to the lateral orbicularis oculi superior muscle, (xii) 1 unit dose to the medial orbicularis oculi superior muscle, (xiii) 1 unit dose to the lateral orbicularis oculi inferior muscle, and / or (xiv) 1 unit dose to the levator palpebrae superioris muscle.

[0210] In any aspect or embodiment of the invention directed to the treatment of atypical hemifacial spasm, the invention may further comprise (i) administering up to 5 unit doses (preferably 1 unit dose) of modified BoNT / A to the frontalis muscle, and optionally 1 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) additional muscles affected by said hemifacial spasm according to the following dosing regimen: (ii) 1 unit dose to the zygomaticus minor muscle, (iii) 1 unit dose to the zygomaticus major muscle, (iv) 1 unit dose to the mentalis muscle, (v) 1 unit dose of modified BoNT / A to the platysma muscle, (vi) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (vii) 1 unit dose to the buccinator muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (ix) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscle, (xi) 1 unit dose to the lateral orbicularis oculi superior muscle, (xii) 1 unit dose to the medial orbicularis oculi superior muscle, (xiii) 1 unit dose to the lateral orbicularis oculi inferior muscle, and / or (xiv) 1 unit dose to the levator palpebrae superioris muscle.

[0211] In any aspect or embodiment of the invention directed to the treatment of atypical hemifacial spasm, the invention may further comprise (i) administering one unit dose of modified BoNT / A to the mentalis muscle affected by said hemifacial spasm, and optionally 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, twelve or more, or thirteen or more) additional muscles affected by said hemifacial spasm, according to the following dosing regimen: (ii) 1 unit dose to the zygomaticus minor muscle, (iii) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (iv) 1 unit dose to the zygomaticus major muscle, (v) 1 unit dose to the platysma muscle, (vi) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (vii) 1 unit dose to the buccinator muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (ix) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscles, (xi) 1 unit dose to the lateral orbicularis oculi superior muscle, (xii) 1 unit dose to the medial orbicularis oculi superior muscle, (xiii) 1 unit dose to the lateral orbicularis oculi inferior muscle, and / or (xiv) 1 unit dose to the levator palpebrae superioris muscle.

[0212] In any aspect or embodiment of the invention directed to the treatment of atypical hemifacial spasm, the invention may further comprise (i) administering one unit dose of modified BoNT / A to the platysma muscle affected by said hemifacial spasm, and optionally 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, twelve or more, or thirteen or more) additional muscles affected by said hemifacial spasm according to the following dosing regimen: (ii) 1 unit dose to the zygomaticus minor muscle, (iii) up to 5 unit doses (preferably 1 unit dose) to the frontalis muscle, (iv) 1 unit dose to the mentalis muscle, (v) 1 unit dose to the zygomaticus major muscle, (vi) up to 2 unit doses (preferably 1 unit dose) to the corrugator supercilii muscle, (vii) 1 unit dose to the buccinator muscle, (viii) up to 2 unit doses (preferably 1 unit dose) to the masseter muscle, (ix) 1 unit dose to the procerus muscle, (x) 1 unit dose to the nasal muscle, (xi) 1 unit dose to the lateral orbicularis oculi superior muscle, (xii) 1 unit dose to the medial orbicularis oculi superior muscle, (xiii) 1 unit dose to the lateral orbicularis oculi inferior muscle, and / or (xiv) 1 unit dose to the levator palpebrae superioris muscle.

[0213] In any aspect or embodiment of the invention directed to the treatment of atypical hemifacial spasm, the invention may fu...

Claims

1. A medicament for use in a method of treating blepharospasm in a subject (e.g., for a longer period of time than treatment with an unmodified BoNT / A (e.g., SEQ ID NO: 2)), wherein the medicament comprises a modified botulinum neurotoxin A (BoNT / A), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, and the method comprises: a) administering a unit dose of the modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to a first eye of the subject; b) administering a unit dose of the modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the first eye of the subject; and c) administering a unit dose of the modified BoNT / A to the proximal lateral inferior orbicularis oculi muscle of the first eye of the subject; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during said treatment is up to 24000 pg of modified BoNT / A; and Here, the modified BoNT / A comprises a light chain and a translocation domain (H N ) and the receptor binding domain of BoNT / B (H C domain) and includes

2. A medicament for use in a method of treating typical hemifacial spasm (e.g., for a longer period of time than treatment with unmodified BoNT / A (e.g., SEQ ID NO: 2)), wherein the medicament comprises a modified botulinum neurotoxin A (BoNT / A), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, and the method comprises: a) administering a unit dose of the modified BoNT / A to the lateral orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; b) administering a unit dose of the modified BoNT / A to the medial orbicularis oculi superior muscle proximal to the eye affected by hemifacial spasm; c) administering a unit dose of the modified BoNT / A to the lateral inferior orbicularis oculi muscle proximal to the eye affected by hemifacial spasm; and d) administering one or more unit doses of said modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during said treatment is up to 24000 pg of modified BoNT / A; and Here, the modified BoNT / A comprises a light chain and a translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C domain) and includes

3. A medicament for use in treating atypical hemifacial spasm in a subject (e.g., for a longer period than treatment with unmodified BoNT / A (e.g., SEQ ID NO: 2)), wherein the medicament comprises a modified botulinum neurotoxin A (BoNT / A), wherein the modified BoNT / A is administered by intramuscular injection to multiple sites on the face of the subject, and the method comprises: a) administering a unit dose of the modified BoNT / A to the orbicularis oris muscle affected by the hemifacial spasm (e.g., administering one unit dose of the modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and / or administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm, preferably administering one unit dose of the modified BoNT / A to the upper orbicularis oris muscle affected by the hemifacial spasm and administering one unit dose to the lower orbicularis oris muscle affected by the hemifacial spasm), and b) optionally administering one or more unit doses of said modified BoNT / A to one or more additional muscles affected by said hemifacial spasm according to the following dosing regimen: (i) 1 unit dose into the zygomaticus major muscle; (ii) 1 unit dose into the zygomaticus minor muscle; (iii) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (iv) 1 unit dose into the mentalis muscle; (v) 1 unit dose into the platysma muscle; (vi) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (vii) 1 unit dose into the buccinator muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (ix) 1 unit dose into the procerus muscle; (x) 1 unit dose into the bridge of the nose, (xi) 1 unit dose into the lateral superior orbicularis oculi muscle; (xii) 1 unit dose into the medial orbicularis oculi superior muscle; (xiii) 1 unit dose into the lateral inferior orbicularis oculi muscle, and / or (xiv) 1 unit dose into the levator palpebrae superioris; wherein the unit dose of modified BoNT / A is at least 240 pg (preferably 240 pg to 8000 pg) of modified BoNT / A; wherein the total dose administered during said treatment is up to 24000 pg of modified BoNT / A; and Here, the modified BoNT / A comprises a light chain and a translocation domain (H) of botulinum neurotoxin A (BoNT / A). N ) and the receptor binding domain of BoNT / B (H C domain) and includes

4. The pharmaceutical composition of any one of claims 1 to 3, further comprising administering one or more unit doses of the modified BoNT / A to one or more additional muscles affected by the blepharospasm according to the following dosing regimen: (i) 1 unit dose into the superior orbicularis oris muscle; (ii) 1 unit dose into the inferior orbicularis oris muscle; (iii) 1 unit dose into the zygomaticus major muscle; (iv) 1 unit dose into the zygomaticus minor muscle; (v) up to 5 unit doses (preferably 1 unit dose) into the frontalis muscle; (vi) 1 unit dose into the mentalis muscle; (vii) 1 unit dose into the platysma muscle; (viii) up to 2 unit doses (preferably 1 unit dose) into the corrugator supercilii; (ix) 1 unit dose into the buccinator muscle; (x) up to 2 unit doses (preferably 1 unit dose) into the masseter muscle; (xi) 1 unit dose into the procerus muscle; (xii) one unit dose into the bridge of the nose, and / or (xiii) 1 unit dose into the levator palpebrae superioris

5. The pharmaceutical composition of any one of claims 1 to 3, further comprising administering one or more unit doses of the modified BoNT / A to one or more additional muscles affected by the blepharospasm according to the following dosing regimen: (i) 1 unit dose into the levator palpebrae superioris

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the unit dose of the modified BoNT / A is 240 pg to 4800 pg of the modified BoNT / A.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the unit dose of the modified BoNT / A is 240 pg to 4000 pg of the modified BoNT / A.

8. The pharmaceutical composition according to any one of claims 1 to 3, wherein the unit dose of the modified BoNT / A is 240 pg to 2400 pg of the modified BoNT / A.

9. The pharmaceutical composition according to any one of claims 1 to 3, wherein the unit dose of the modified BoNT / A is 240 pg to 2000 pg of the modified BoNT / A.

10. The pharmaceutical composition according to any one of claims 1 to 3, wherein the unit dose (e.g., the lower limit of the unit dose) is at least 500 pg of modified BoNT / A.

11. The pharmaceutical composition according to any one of claims 1 to 3, wherein the unit dose (e.g., the lower limit of the single unit dose) is at least 1000 pg of modified BoNT / A.

12. The pharmaceutical of any one of claims 1 to 3, wherein the modified BoNT / A comprises a polypeptide sequence having at least 70% sequence identity to SEQ ID NO:

14.

13. The pharmaceutical of any one of claims 1 to 3, wherein the modified BoNT / A comprises a combination of two substitution mutations, E1191M and S1199Y.

14. The pharmaceutical of any one of claims 1 to 3, wherein the modified BoNT / A is a two-chain modified BoNT / A in which a light chain (L chain) is linked to the resulting heavy chain (H chain) via a disulfide bond, and which can be obtained by a method comprising contacting a single-chain modified BoNT / A comprising SEQ ID NO: 14 with a protease that hydrolyzes the peptide bond in its activation loop, thereby converting the single-chain modified BoNT / A into the corresponding two-chain modified BoNT / A.

15. The pharmaceutical of any one of claims 1 to 3, wherein the modified BoNT / A is a two-chain modified BoNT / A in which the L chain is linked to the resulting H chain via a disulfide bond, and which can be obtained by a method comprising contacting a single-chain modified BoNT / A consisting of SEQ ID NO: 14 with a protease that hydrolyzes the peptide bond in its activation loop, thereby converting the single-chain modified BoNT / A into the corresponding two-chain modified BoNT / A.

16. The method of any one of claims 1 to 3, wherein the modified BoNT / A is administered in a single unit dose per injection site.

17. The pharmaceutical according to any one of claims 1 to 3, wherein the subject is a human subject.

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