Uses of iron chelators for treating stuttering

Abstract

Provided herein are uses of iron chelators to treat stuttering. The iron chelators include deferiprone, deferoxamine, and deferasirox.

Description

USES OF IRON CHELATORS FOR TREATING STUTTERINGSTATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made in part with Government support under NIH ZIA NS009420. The Government has certain rights in this invention.FIELD OF THE INVENTION

[0002] The present invention relates to the use of iron chelators to treat stuttering. The iron chelators include deferiprone, deferoxamine, and deferasirox.BACKGROUND OF THE INVENTION

[0003] The American Psychiatric Association (APA) defines childhood-onset fluency disorder (also known as stuttering) as a persistent disruption in the normal fluency and time pattern of speech that is not appropriate for the individual’s age. Stuttering is the most frequent type of speech disorder and is considered a neurodevel opmental motor disorder. People who stutter may struggle with a lower quality of life, face educational and occupation barriers, and be denied access to quality treatment plans. Although stuttering affects about 1% of the adult U.S. population, it is estimated that approximately 10% of the population at some point in their life are challenged by speech disorders. Stuttering is present in all cultural, racial, ethnic, and economic groups studied. It is a highly inheritable disorder, as genetic factors contribute to more than 80% of cases. While stuttering has been known for centuries, its etiology is not fully understood, and no treatment has yet to be approved by the Food and Drug Administration (or other federal government agencies) to improve the quality of life in people who stutter. Accordingly, there is a need in the art for therapeutics to treat stuttering.SUMMARY OF THE INVENTION

[0004] Provided herein is a method of treating a stutter in a subject in need thereof. The method may comprise administering to the subject a composition comprising an iron chelator. Also provided herein are use of the composition in the manufacture of a medicament for treating a stutter and the composition for treating a stutter. The composition may comprise apharmaceutically acceptable excipient. The iron chelator may comprise one or more of deferiprone; deferoxamine; deferasirox; lactoferrin; ethylenediaminetetraacetic acid (EDTA); diethylenetriaminepentaacetic acid (DTP A); a siderophore; N-hydroxyalkyl-substituted deferiprone; deferoxamine conjugated to poly(ethylene glycol)poly(aspartic acid) block copolymers; deferoxamine conjugated to hydroxyethyl starch; deferitrin; CN128; and PBT434.

[0005] The iron chelator may comprise deferiprone. The deferiprone may be administered or intended to be administered orally. The deferiprone may be administered or intended to be administered at a dose of about 20-100 mg / kg daily.

[0006] The iron chelator may comprise deferoxamine. The deferoxamine may be administered or intended to be administered parentally. The parental administration may be subcutaneous or intravenous. The deferoxamine may be administered or intended to be administered at a dose of about 20-60 mg / kg daily.

[0007] The iron chelator may comprise deferasirox. The deferasirox may be administered or intended to be administered orally. The deferasirox may be administered or intended to be administered at a dose of about 20-30 mg / kg daily.

[0008] Provided herein is a method of treating a stutter in a subject in need thereof, which may comprise orally administering to the subject a composition comprising deferiprone and a pharmaceutically excipient. Also provided are use of the composition in the manufacture of a medicament for treating a stutter and the composition for use in treating a stutter. The medicament or composition may be intended for oral administration. The deferiprone may be administered or intended to be administered at a dose of about 2-100 mg / kg daily, or a dose of about 25-33 mg / kg three times daily.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIGS. 1A-E show that iron is accumulated in Gnptab-mutant mice. FIG. 1A. A brain of a wild-type mouse. FIG. IB shows iron accumulation of a Gnptab-mutant mouse. FIGS. 1C-1E shows statistically significant accumulation of iron in the mediolateral striatum (FIG. 1C), central striatum (FIG. ID), and dorsolateral striatum (FIG. IE) of Gnptab-mutant mice as compared to controls.

[0010] FIGS. 2A-D show that deferiprone (DFP) treatment improved deficits of vocal and grooming behaviors in Gnptab-mutant male mice. FIG. 2A shows the study schematic. FIGs. 2B-C show that iron content decreases in the brains of Gnptap-mutant mice after DFP treatment (FIG. 2C) as compared to before treatment (FIG. 2B). FIG. 2D shows quantification of compound vocalization in wild-type and Gnptab-mutant mice treated with DFP.

[0011] FIGS. 3 A-B show that administering DFP to Gnptab-mutant mice for 30 days improves vocal deficits. FIG. 3A shows the experimental scheme. FIG. 3B shows the results as measured by compound vocalization.

[0012] FIGS. 4A-B show that administering DFP to Gnptab-mutant mice for 60 days improves vocal deficits. FIG. 4A shows the experimental scheme. FIG. 4B shows the results as measured by compound vocalization.

[0013] FIGS. 5A-B show that administering DFP to Gnptab-mutant mice improves vocal deficits, which worsen after discontinuing treatment. FIG. 5A shows the experimental scheme. FIG. 5B shows the results as measured by compound vocalization.DETAILED DESCRIPTION

[0014] Increased iron accumulation has been proposed to be an indirect marker of excess dopamine levels in subjects who stutter. Researchers have theorized that the excess dopamine levels are causative rather than iron, and that the increased dopamine levels may result from lysosomal dysfunction. In other disorders associated elevated iron levels, such as neurodegeneration with brain iron accumulation (NBIA) diseases, iron chelators have yet to yield clinically meaningful benefits. For example, in pantothenate kinase-associated neurodegeneration (PKAN), clinical trials on deferoxamine have not achieved primary endpoints. And worsening of symptoms have been observed in clinical trials on the use of iron chelators for treating PKAN, beta-propeller protein-associated neurodegeneration (BP AN), and neuroferritinopathy. Increased iron content in nigrostriatal neurons has been implicated in the pathophysiology of Parkinson’s Disease (PD). Still, a clinical trial testing the effects of deferiprone in PD patients showed that although iron levels decreased in the brains of treated patients as compared to placebo, both primary and secondary outcomes related to motor and nonmotor symptoms of PD worsened. Thus, the prospects of the efficacy of an iron chelator for treating a brain disease associated with elevated iron levels is unpredictable. But the inventors have discovered that, surprisingly, an iron chelator can treat one or more symptoms of stuttering.1. Definitions.

[0015] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0016] For recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6,9, and 7.0 are explicitly contemplated.

[0017] As used herein, the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. For example, the endpoint may be within 10%, 8%, 5%, 3%, 2%, or 1% of the listed value. Further, for the sake of convenience and brevity, a numerical range of “about 50 mg / mL to about 80 mg / mL” should also be understood to provide support for the range of “50 mg / mL to 80 mg / mL.” The endpoint may also be based on the variability allowed by an appropriate regulatory body, such as the FDA, USP, etc.

[0018] As used herein, “comprises,” “comprising,” “containing,” and “having” and the like may have the meaning ascribed to them in U.S. Patent Law and may mean “includes,” “including,” and the like, and are generally interpreted to be open ended terms. The terms “consisting of’ or “consists of’ are closed terms, and include only the components, structures, steps, or the like specifically listed in conjunction with such terms, as well as that which is in accordance with U.S. Patent law. “Consisting essentially of’ or “consists essentially of’ have the meaning generally ascribed to them by U.S. Patent law. In particular, such terms are generally closed terms, with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the composition’s nature or characteristics would be permissible if present under the “consisting essentially of’ language, even though not expressly recited in a list of items following such terminology. In this specification when using an open-ended term, like “comprising” or “including,” it is understood that direct support should be afforded also to“consisting essentially of’ language as well as “consisting of’ language as if stated explicitly and vice versa.

[0019] As used herein, “pharmaceutically acceptable” may denote an attribute of a material which is useful in preparing a pharmaceutical composition or pharmaceutical formulation that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use. “Pharmaceutically acceptable” can refer to a material, such as a carrier, or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, e.g., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0020] As used herein, “pharmaceutically acceptable excipient” may refer to any pharmaceutically acceptable ingredient in a pharmaceutical composition or pharmaceutical formulation having no therapeutic activity and being non-toxic to the subject administered, such as disintegrators, binders, fdlers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, carriers, diluents, excipients, preservatives or lubricants used in formulating pharmaceutical products.

[0021] As used herein, the terms “subject,” “individual,” and “patient” are used interchangeably. None of the terms are to be interpreted as requiring the supervision of a medical professional (e.g., a doctor, nurse, physician’s assistant, orderly, hospice worker). As used herein, the subject may be any animal, including a mammal (e.g., a human or non-human animal) or a nonmammal. In one embodiment, the subject is a human.

[0022] As used herein, the terms “treat,” “treating,” or “treatment,” and other grammatical equivalents, include ameliorating the underlying causes of one or more symptoms of a disease or condition; alleviating, abating, or ameliorating one or more symptoms of a disease or condition; decreasing comorbidities associated with a disease or condition; ameliorating or reducing the appearance, severity, or frequency of one or more symptoms of a disease or condition; inhibiting the disease or condition, such as, for example, arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or inhibiting the symptoms of the disease or condition either prophylactically and / or therapeutically. Methods of treatment as disclosed herein include disclosures of the use of the compounds, pharmaceutical compositions,or pharmaceutical formulations provided herein for the treatment of any indication described herein, and include disclosures of the compounds, pharmaceutical compositions, or pharmaceutical formulations provided herein for the use in treating any indication described herein.2. Methods of treating stuttering

[0023] Provided herein is a method of treating stuttering, which may comprise administering a composition comprising an iron chelator to a subject in need thereof. The composition may comprise a pharmaceutically acceptable excipient. Further provided are the composition for treating stuttering, and use of the iron chelator in the manufacture of a medicament for treating stuttering. The subject may be an adult (at least 18 years of age) or a juvenile (younger than 18 years of age).

[0024] The iron chelator may be deferiprone; deferoxamine (which may be deferoxamine mesylate); deferasirox; lactoferrin; ethylenediaminetetraacetic acid (EDTA); diethylenetriaminepentaacetic acid (DTP A); a siderophore; N-hydroxyalkyl-substituted deferiprone; polymeric deferoxamine, which may comprise deferoxamine conjugated to poly(ethylene glycol)poly(aspartic acid) block copolymers; deferoxamine conjugated to hydroxyethyl starch; deferitrin; CN128; or PBT434. The iron chelator may be an active isomer, prodrug, active metabolite, deuterated form, pharmaceutically acceptable salt, extended-release form, or racemic mixture of an iron chelator disclosed herein. In one example, the iron chelator is deferiprone (DFP).

[0025] Two or more iron chelators may be used in combination. The iron chelators may be administered simultaneously or sequentially. In one example, deferoxamine and deferasirox are co-administered. In another example, deferoxamine and deferiprone are co-administered. In one example, deferasirox is co-administered with deferiprone.

[0026] Pharmaceutically acceptable excipients for iron chelators are known in the art. The pharmaceutically acceptable excipient may be suitable for oral or sublingual administration, and may comprise one or more of colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, crospovidone, povidone (which may be K30), colloidal anhydrous silica, and pol oxamer 188. In one example, the composition is FERRIPROX®. In one example, the composition is EXJADE®. The pharmaceutically acceptable excipient may be suitable for parenteral administration and may comprise sterile water for injection, sodium chloride solution(which may comprise 0.9% or 0.45% sodium chloride), dextrose solution (which may comprise 5% dextrose), or lactated Ringers solution. The composition may be DESFERAL®.

[0027] The iron chelator may be administered parenterally, orally, sublingually, intramuscularly, intravenously, rectally, vaginally, via inhalation, intranasally, intrathecally, topically, subcutaneously, transdermally, buccally, epidurally, or intracerebroventricularly. In one example, the iron chelator is administered orally or sublingually. The deferiprone may be administered orally, intravenously, or intramuscularly. In one example, the deferiprone may be administered orally. The deferiprone may be administered at a dose of about 20-100 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 90 mg / kg, 99 mg / kg, 100 mg / kg, or a range of the foregoing including 20-30 mg / kg, 70-100 mg / kg, 75-100 mg / kg, or 70-80 mg / kg, which may be daily. Deferoxamine may be administered parenterally, which may be subcutaneously or intravenously. The deferoxamine may be administered at a dose of about 1-2 g; or about 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, or a range of the foregoing, including 20-60 mg / kg or 20-40 mg / kg, which may be daily. The deferasirox may be administered orally. The deferasirox may be administered at a dose of about 20-30 mg / kg, which may be daily.

[0028] Stuttering may be a childhood onset speech fluency disorder. The stuttering may be associated with one or more alterations in speech- or language-based circuits. The alteration may comprise dysfunction in basal ganglia of a brain of a subject who stutters. The alteration may be a deficit in a corti co-striatal-thalamo-cortical loop that connects cortical regions of a brain to motor circuits of basal ganglia to a relay station in the thalamus. A speech network of a brain of a subject who stutters may exhibit increased iron content as compared to fluent-speaking people. The increased iron content may be measured by performing magnetic resonance imaging (MRI) using effective transverse relaxation rate (R2*). R2* may correlate with the amount of iron deposits in grey matter. The subject who stutters may exhibit increased iron accumulation in one or more of the corpus collosum, dorsolateral striatum, and central striatum. The increased iron accumulation may be in astrocytes.

[0029] The one or more iron chelators described herein may decrease the R2* in a subject’s brain, particularly in basal ganglia. The one or more iron chelators may decrease the amount of iron in one or more of the corpus collosum, dorsolateral striatum, and central striatum of thesubject who stutters. The one or more iron chelators may decrease the amount of iron in astrocytes.

[0030] The present invention has multiple aspects, illustrated by the following non-limiting examples.Example 1 Iron chelators effectively improve stuttering symptoms in model mice

[0031] This example demonstrates that an iron chelator disclosed herein effectively treats stuttering in model mice. The animal subjects used for this study were a total of 21 mice, aged between 3 to 5 months. The group was divided into control mice (n = 9) and Gnptab-mutant mice (n = 12). The animals were housed in controlled temperature and humidity conditions, under a 12: 12 light-dark cycle. Both groups were maintained on a standard diet throughout the study period. Iron-chelator DFP (Deferiprone; Sigma) was used as the experimental drug. The DFP was administered to both groups of mice through their drinking water at a concentration of 50 mg / L (which translates to 8-13 mg of DFP per day depending on the animal’s weight), starting from day zero for a period of 30 days. The vocal behaviors of both the control and Gnptab-mutant mice were recorded using a high-frequency microphone sensitive to the ultrasonic vocalizations produced by the mice. The recorded vocalizations were analyzed by a custom-made Python package for analysis of the frequency, duration, and geometry of the vocalizations. Behavioral observations were carried out at two distinct time-points. The baseline vocal behaviors were recorded prior to the commencement of the DFP administration. The posttreatment vocal behaviors were then recorded 30 days following the initiation of the DFP administration.

[0032] FIG 1 shows iron deposition in Gnptab-mutant mice. Perl’s staining was used to identify iron deposits in the brain of the control (FIG. 1A) and Gnptab-mutant (FIG. IB) mice. Comparable sections from control and Gnptab-mutant mice at the level of striatum is shown. FIGs. 1C-1E show quantification of iron content at different sections of the striatum in mutant vs. control mice (n = 4 mice per group).

[0033] FIG. 2 shows that DFP improved vocal deficits in Gnptab-mutant mice. FIG 2A shows schematics of DFP treatment. Mice were treated with DFP (8-13 mg / kg body weight) over 30 consecutive days. Vocal behaviors were recorded on Day 0 and 30. Oral administration of DFPdecreased iron content in the brain (FIG.2B: before DFP treatment; FIG. 2C: after DFP treatment). Quantification of compound vocalization (which is used as an index of stuttering in mice) showed significant decrease in percentage of compound vocalization in Gnptab-mutant mice that received DFP treatment (FIG. 2D). N = 9-12 mice per group.

[0034] These data directly show that iron is accumulated in the brain of adult Gnptab-mutant mice. The analysis also shows that iron is mainly accumulated in the basal ganglia, particularly striatum. Possible involvement of striatum in pathophysiology of developmental stuttering has been suggested from several imaging studies on people who stutter. The results above suggest that oral iron chelator treatments decreased iron content at the striatum level (FIGs. 2B-C) and improves deficits in vocal behaviors (i.e., decrease in percentage of compound vocalization) in Gnptab-mutant mice when compared to the control litter mates.Example 2 Iron chelators effectively improve stuttering symptoms in model mice

[0035] This example demonstrates that an iron chelator disclosed herein effectively treats stuttering in model mice. The animal subjects used for this study were a total of 12 mice, aged between 2.5 to 4 months. The group was divided into control mice (n = 6) and Gnptab-mutant mice (n = 6). The animals were housed in controlled temperature and humidity conditions, under a 12:12 light-dark cycle. Both groups were maintained on a standard diet throughout the study period. Iron-chelator DFP (Deferiprone; Sigma) was used as the experimental drug. The DFP was administered to both groups of mice through their drinking water at a concentration of 50 mg / L (which translates to 8-13 mg of DFP per day depending on the animal’s weight), starting from day zero for a period of 30 days. The vocal behaviors of both the control and Gnptab-mutant mice were recorded using a high-frequency microphone sensitive to the ultrasonic vocalizations produced by the mice. The recorded vocalizations were analyzed by a custom-made Python package for analysis of the frequency, duration, and geometry of the vocalizations. Behavioral observations were carried out at two distinct time-points. The baseline vocal behaviors were recorded prior to the commencement of the DFP administration. The posttreatment vocal behaviors were then recorded 30 days following the initiation of the DFP administration.

[0036] FIG. 3 shows that DFP improved vocal deficits in Gnptab-mutant mice. FIG 3A shows schematics of DFP treatment. Mice were treated with DFP (8-13 mg / kg body weight) over 30 consecutive days. Vocal behaviors were recorded on Day 0 and 30. Quantification of compound vocalization (which is used as an index of stuttering in mice) showed a significant decrease in percentage of compound vocalization in Gnptab-mutant mice that received DFP treatment (FIG. 3B). N = 6 mice per group.Example 3 Iron chelators effectively improve stuttering symptoms in model mice

[0037] This example demonstrates that an iron chelator disclosed herein effectively treats stuttering in model mice. The animal subjects used for this study were a total of 10 mice, aged between 3 to 5 months. The group was divided into control mice (n = 5) and Gnptab-mutant mice (n = 5). The animals were housed in controlled temperature and humidity conditions, under a 12: 12 light-dark cycle. Both groups were maintained on a standard diet throughout the study period. Iron-chelator DFP (Deferiprone; Sigma) was used as the experimental drug. The DFP was administered to both groups of mice through their drinking water at a concentration of 50 mg / L (which translates to 8-13 mg of DFP per day depending on the animal’s weight), starting from day zero for a period of 60 days. The vocal behaviors of both the control and Gnptab-mutant mice were recorded using a high-frequency microphone sensitive to the ultrasonic vocalizations produced by the mice. The recorded vocalizations were analyzed by a custom-made Python package for analysis of the frequency, duration, and geometry of the vocalizations. Behavioral observations were carried out at two distinct time points. The baseline vocal behaviors were recorded prior to the commencement of the DFP administration. The posttreatment vocal behaviors were then recorded 60 days following the initiation of the DFP administration.

[0038] FIG. 4 shows that DFP improved vocal deficits in Gnptab-mutant mice. FIG 4A shows schematics of DFP treatment. Mice were treated with DFP (8-13 mg / kg body weight) over 60 consecutive days. Vocal behaviors were recorded on Day 0 and 60. Quantification of compound vocalization (which is used as an index of stuttering in mice) showed a significant decrease in percentage of compound vocalization in Gnptab-mutant mice that received DFP treatment (FIG. 3B). N = 5 mice per group.Example 4Iron chelators effectively improve stuttering symptoms in model mice

[0039] This example demonstrates that an iron chelator disclosed herein effectively treats stuttering in model mice. The animal subjects used for this study were a total of 12 mice, aged between 3 to 5 months. The group was divided into control mice (n = 6) and Gnptab-mutant mice (n = 6). The animals were housed in controlled temperature and humidity conditions, under a 12: 12 light-dark cycle. Both groups were maintained on a standard diet throughout the study period. Iron-chelator DFP (Deferiprone; Sigma) was used as the experimental drug. The DFP was administered to both groups of mice through their drinking water at a concentration of 50 mg / L (which translates to 8-13 mg of DFP per day depending on the animal’s weight), starting from day zero for a period of 30 days. The vocal behaviors of both the control and Gnptab-mutant mice were recorded using a high-frequency microphone sensitive to the ultrasonic vocalizations produced by the mice. The recorded vocalizations were analyzed by a custom-made Python package for analysis of the frequency, duration, and geometry of the vocalizations. Behavioral observations were carried out at three distinct time points. The baseline vocal behaviors were recorded prior to the commencement of the DFP administration. The DFP- treatment vocal behaviors were recorded 30 days following the initiation of the DFP administration. Post-treatment vocal behaviors were then recorded 30 days after the last dose of DFP -treatment

[0040] FIG. 5 shows that DFP improved vocal deficits in Gnptab-mutant mice. FIG 5A shows schematics of DFP treatment. Mice were treated with DFP (8-13 mg / kg body weight) over 30 consecutive days. Vocal behaviors were recorded on Day 0, 30 and 60. Quantification of compound vocalization (which is used as an index of stuttering in mice) showed a significant decrease in percentage of compound vocalization in Gnptab-mutant mice that received DFP treatment (FIG. 5B). However, the percentage of compound vocalization increased 30 days after the last does of treatment. N = 6 mice per group.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a stutter in a subject in need thereof, comprising administering to the subject a composition comprising an iron chelator.

2. The method of claim 1, wherein the composition comprises a pharmaceutically acceptable excipient.

3. The method of claim 1, wherein the iron chelator is selected from the group consisting of deferiprone; deferoxamine; deferasirox; lactoferrin; ethylenediaminetetraacetic acid (EDTA); diethylenetriaminepentaacetic acid (DTP A); a siderophore; N-hydroxyalkyl-substituted deferiprone; deferoxamine conjugated to polyethylene glycol)poly(aspartic acid) block copolymers; deferoxamine conjugated to hydroxyethyl starch; deferitrin; CN128; and PBT434.

4. The method of claim 3, wherein the iron chelator is deferiprone.

5. The method of claim 4, wherein the deferiprone is administered orally.

6. The method of claim 5, wherein the deferiprone is administered at a dose of about20-100 mg / kg daily.

7. The method of claim 3, wherein the iron chelator is deferoxamine.

8. The method of claim 7, wherein the deferoxamine is administered parenterally.

9. The method of claim 8, wherein the deferoxamine is administered subcutaneously or intravenously.

10. The method of claim 9, wherein the deferoxamine is administered at a dose of about 20-60 mg / kg daily.

11. The method of claim 3, wherein the iron chelator is deferasirox.

12. The method of claim 11, wherein the deferasirox is administered orally.

13. The method of claim 12, wherein the deferasirox is administered at a dose of about 20-30 mg / kg daily.

14. A method of treating a stutter in a subject in need thereof comprising orally administering to the subject a composition comprising deferiprone and a pharmaceutically acceptable excipient.

15. The method of claim 14, wherein the deferiprone is administered at a dose of about 20-100 mg / kg daily.

16. The method of claim 15, wherein the deferiprone is administered at dose of about 25-33 mg / kg three times daily.

17. A composition comprising an iron chelator for treating a stutter.

18. The composition of claim 17, wherein the composition comprises a pharmaceutically acceptable excipient.

19. The composition of claim 17, wherein the iron chelator is selected from the group consisting of deferiprone; deferoxamine; deferasirox; lactoferrin; ethylenediaminetetraacetic acid (EDTA); diethylenetriaminepentaacetic acid (DTP A); a siderophore; N-hydroxyalkyl-substituteddeferiprone; deferoxamine conjugated to polyethylene glycol)poly(aspartic acid) block copolymers; deferoxamine conjugated to hydroxyethyl starch; deferitrin; CN128; and PBT434.

20. The composition of claim 19, wherein the iron chelator is deferiprone.

21. The composition of claim 20, wherein the deferiprone is administered orally.

22. The composition of claim 21, wherein the deferiprone is administered at a dose of about 20-100 mg / kg daily.

23. The composition of claim 19, wherein the iron chelator is deferoxamine.

24. The composition of claim 23, wherein the deferoxamine is administered parenterally.

25. The composition of claim 24, wherein the deferoxamine is administered subcutaneously or intravenously.

26. The composition of claim 25, wherein the deferoxamine is administered at a dose of about 20-60 mg / kg daily.

27. The composition of claim 19, wherein the iron chelator is deferasirox.

28. The composition of claim 27, wherein the deferasirox is administered orally.

29. The composition of claim 28, wherein the deferasirox is administered at a dose of about 20-30 mg / kg daily.

30. A composition comprising deferiprone and a pharmaceutically acceptable excipient for treating a stutter, wherein the composition is for oral administration.31 . The composition of claim 30, wherein the deferiprone is administered at a dose of about 20-100 mg / kg daily.

32. The composition of claim 31, wherein the deferiprone is administered at dose of about 25-33 mg / kg three times daily.

33. Use of a composition comprising an iron chelator in the manufacture of a medicament for treating a stutter.

34. The use of claim 33, wherein the composition comprises a pharmaceutically acceptable excipient.

35. The use of claim 33, wherein the iron chelator is selected from the group consisting of deferiprone; deferoxamine; deferasirox; lactoferrin; ethylenediaminetetraacetic acid (EDTA); diethylenetriaminepentaacetic acid (DTP A); a siderophore; N-hydroxyalkyl-substituted deferiprone; deferoxamine conjugated to polyethylene glycol)poly(aspartic acid) block copolymers; deferoxamine conjugated to hydroxyethyl starch; deferitrin; CN128; and PBT434.

36. The use of claim 35, wherein the iron chelator is deferiprone.

37. The use of claim 36, wherein the deferiprone is administered orally.

38. The use of claim 37, wherein the deferiprone is administered at a dose of about20-100 mg / kg daily.

39. The use of claim 35, wherein the iron chelator is deferoxamine.

40. The use of claim 39, wherein the deferoxamine is administered parenterally.41 . The use of claim 40, wherein the deferoxamine is administered subcutaneously or intravenously.

42. The use of claim 41, wherein the deferoxamine is administered at a dose of about 20-60 mg / kg daily.

43. The use of claim 35, wherein the iron chelator is deferasirox.

44. The use of claim 43, wherein the deferasirox is administered orally.

45. The use of claim 44, wherein the deferasirox is administered at a dose of about20-30 mg / kg daily.

46. Use of a composition comprising deferiprone and a pharmaceutically acceptable excipient in the manufacture of a medicament for treating a stutter, wherein the medicament is for oral administration.

47. The use of claim 46, wherein the deferiprone is administered at a dose of about 20-100 mg / kg daily.

48. The use of claim 47, wherein the deferiprone is administered at dose of about 25-33 mg / kg three times daily.

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