Compositions and methods for the treatment of amyotrophic lateral sclerosis, Parkinson's disease, Parkinson's disease with dementia, dementia with Lewy bodies, and multiple system atrophy
The present disclosure provides novel methods for treating or preventing amyotrophic lateral sclerosis (ALS), methods for delaying the onset of neurological symptoms associated with ALS, increasing survival in subjects afflicted with ALS, and attenuating the decline of muscle strength associated with ALS in a subject in need thereof. The present disclosure also provides methods for treating or preventing α-synucleinopathy or TDP-43 proteinopathy. The methods comprise administering to the subject an effective amount of a mitochondria-targeting peptidomimetic compound, such as (R)-2-amino-N—((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
1. A method for treating or inhibiting α-synucleinopathy or TAR DNA binding protein 43 (TDP-43) proteinopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptidomimetic (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl) -1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and/or solvate thereof.
2. The method of claim 1 , wherein the subject has been diagnosed as having an α-synucleinopathy or a TDP-43 proteinopathy.
3. The method of claim 2 , wherein the a-synucleinopathy is Parkinson's Disease (PD), PD with dementia, dementia with Lewy bodies, or Multiple System Atrophy (MSA).
4. The method of claim 2 , wherein the TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS) or Frontotemporal Lobar Degeneration (FTLD).
5. The method of claim 1 , wherein the peptidomimetic is administered daily for 2 weeks or more.
6. The method of claim 1 , wherein the peptidomimetic is administered daily for 12 weeks or more.
7. The method of claim 1 , wherein the treating or inhibiting of α-synucleinopathy comprises attenuating the loss of dopaminergic neurons in the subject as compared to untreated controls.
8. The method of claim 1 , wherein the treating or inhibiting of TDP-43 proteinopathy comprises an increase in neurite length in the subject as compared to untreated controls.
9. The method of claim 1 , wherein the subject is a mammal.
10. The method of claim 9 , wherein the mammalian subject is a human.
11. The method of claim 1 , wherein the peptidomimetic is administered orally or subcutaneously.
12. The method of claim 1 , wherein the peptidomimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.
13. The method of claim 1 , further comprising separately, sequentially, or simultaneously administering an additional treatment to the subject.
14. The method of claim 13 , wherein the additional treatment comprises administration of a therapeutic agent.
15. The method of claim 14 , wherein the therapeutic agent comprises levodopa for the treatment of α-synucleinopathy, and wherein the therapeutic agent comprises a selective serotonin reuptake inhibitor (SSRI) antidepressant for the treatment of TDP-43 proteinopathy.
16. The method of claim 13 , wherein the combination of peptidomimetic and an additional therapeutic treatment has a synergistic effect in the prevention or treatment of α-synucleinopathy or TDP-43 proteinopathy.
17. The method of claim 1 , wherein the pharmaceutically acceptable salt comprises a tartrate salt, a fumarate salt, monoacetate salt, a bis-acetate salt, a tri-acetate salt, a mono-trifluoroacetate salt, a bis-trifluoroacetate salt, a trifluoroacetate salt, a monohydrochloride salt, a bis-hydrochloride salt, a trihydrochloride salt, a mono-tosylate salt, a bis-tosylate salt, or a tri-tosylate salt.
18. The method of claim 1 , wherein the peptidomimetic is formulated as a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.