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Publication Number
US-12144792-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present disclosure provides for treating neurodegenerative diseases comprising administering acetyl-leucine or a pharmaceutically acceptable salt thereof.
Core Innovation
The disclosure presents acetyl-leucine as a neuroprotective therapeutic for a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease. Acetyl-leucine is described in racemate and enantiomeric forms, including acetyl-DL-leucine, acetyl-L-leucine, and acetyl-D-leucine, and includes pharmaceutically acceptable salts. The therapeutic use covers subjects having, suspected of having, or at risk of having a neurodegenerative disease, as well as subjects in need of treatment for disease or symptoms.
A key aspect of the disclosure is patient and disease selection. In certain embodiments, the neurodegenerative disease is not cerebellar ataxia and not Niemann-Pick Type C. The treated neurodegenerative disease is chosen from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple system atrophy type P (MSA-P), multiple system atrophy type C (MSA-C), frontotemporal dementia with parkinsonism, progressive supranuclear palsy, corticobasal degeneration, Lewy Body dementia, Parkinson's Disease, and ataxia telangiectasia (Louis Barr disease).
The disclosure additionally frames acetyl-leucine treatment as delaying onset, delaying progression, reversing progression, and reducing severity, with neuroprotection over extended durations. The disclosure describes targeting lysosomal dysfunction and lysosomal storage disorders, and includes lysosomal volume and downstream biomarkers as mechanistic markers, including reduction of lysosomal volume and changes in glycosphingolipids (GSLs), LC3-II, and amyloid precursor protein C-terminal fragments (APP-CTFs), consistent with improved autophagic flux and downstream pathology markers.
Claims Coverage
The document provides six independent claims for treating disease or symptoms, delaying progression, reversing progression, reducing severity, and providing neuroprotection. Across the independent claims, the inventive coverage centers on administering acetyl-leucine or a pharmaceutically acceptable salt for specified durations in a defined set of neurodegenerative diseases, with explicit exclusion of cerebellar ataxia and Niemann-Pick Type C.
Acetyl-leucine administration for selected neurodegenerative diseases excluding cerebellar ataxia and Niemann-Pick Type C
Administering a therapeutically effective amount of acetyl-leucine or a pharmaceutically acceptable salt thereof for a duration of at least 3 months, or at least about 6 months, at least about 1 year, at least about 2 years, or at least about 5 years, to a subject with a neurodegenerative disease chosen from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple system atrophy type P (MSA-P), multiple system atrophy type C (MSA-C), frontotemporal dementia with parkinsonism, progressive supranuclear palsy, corticobasal degeneration, Lewy Body dementia, Parkinson's Disease, and ataxia telangiectasia (Louis Barr disease), with explicit exclusion of cerebellar ataxia and Niemann-Pick Type C.
Disease progression and severity modification
The method delays progression of a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease over time as compared to typical disease progression, reverses progression of a neurodegenerative disease or one or more symptoms associated with a neurodegenerative disease over time, and reduces the severity of a neurodegenerative disease or reducing the severity of or eliminating one or more existing symptoms associated with a neurodegenerative disease.
Neuroprotection
The method provides neuroprotection in a subject having, suspected of having, or at risk of having a neurodegenerative disease.
Across the independent claims, the claimed inventive scope is defined by administering acetyl-leucine or a pharmaceutically acceptable salt to treat, delay progression, reverse progression, reduce severity, or provide neuroprotection in a defined set of neurodegenerative diseases, while explicitly excluding cerebellar ataxia and Niemann-Pick Type C.
Stated Advantages
Delaying onset.
Delaying progression.
Reversing progression.
Reducing severity.
Providing neuroprotection.
Improving biochemical markers, including reduction of lysosomal volume, reduction of glycosphingolipids (GSL) storage-related markers, and changes in LC3-II and APP-CTFs.
Documented Applications
Neuroprotection and treatment of neurodegenerative diseases associated with lysosomal dysfunction and lysosomal storage disorders, including Niemann-Pick Type C (NPC), Niemann-Pick disease forms referenced in the disclosure, and other lysosomal storage disorders listed in the disclosure (e.g., Tay-Sachs/Sandhoff, GM2, GM1).
In vivo phenotypic improvement in an NPC mouse model (Npc1−/−), including gait, weight, and lifespan improvements.
Improvement in a Sandhoff mouse (Hexb−/−), including increased lifespan and motor improvements.
Reduction of lysosomal volume in patient fibroblasts.
In patient context, outcomes described as slowed progression in NPC patient case reports, including clinical severity score (CSS) and annual severity increment score (ASIS) outcomes.
Tissue study outcomes in NPC mouse tissue, including reduced APP-CTFs and LC3-II consistent with improved AD-like pathology and autophagic flux.
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