DNP and DNP prodrug treatment of neuromuscular, neurodegenerative, autoimmune, developmental, traumatic brain injury, concussion, dry eye disease, hearing loss and/or metabolic diseases
Inventors
Geisler, John Gerard • Alonso, Robert • Crooks, Peter Anthony • Penthala, Narsimha Reddy • Albayati, Zaineb
Assignees
BioVentures LLC • Mitochon Pharmaceuticals Inc
Publication Number
US-11406642-B2
Publication Date
2022-08-09
Expiration Date
2037-03-07
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Abstract
A composition and method of treatment of neuromuscular, neuromuscular degenerative, neurodegenerative, autoimmune, developmental, traumatic, hearing loss related, and/or metabolic diseases, including spinal muscular atrophy (SMA) syndrome (SMA1, SMA2, SMA3, and SMA4, also called Type I, II, III and IV), traumatic brain injury (TBI), concussion, keratoconjunctivitis sicca (Dry Eye Disease), glaucoma, Sjogren's syndrome, rheumatoid arthritis, post-LASIK surgery, anti-depressants use, Wolfram Syndrome, and Wolcott-Rallison syndrome. The composition is selected from the group consisting of 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP, bipartite 2,3-dinitrophenol, 2,4-dinitrophenol, 2,5-dinitrophenol, 2,6-dinitrophenol, 3,4-dinitrophenol, or 3,5-dinitrophenol (2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP) prodrugs; Gemini prodrugs, bioprecursor molecules, and combinations thereof. A dose of the composition for treatment of neurodegenerative diseases may be from about 0.01 mg/kg of body weight to about 50 mg/kg of body weight of the patient in need of treatment. A dose of the composition for treatment of metabolic diseases may be from about 1 mg/70 kg of body weight to about 100 mg/70 kg of body weight of the patient in need of treatment, and a maximum dose per day is about 200 mg/70 kg of body weight of the patient in need of treatment.
Core Innovation
The invention provides compositions and methods for treating a broad range of diseases including neuromuscular, neuromuscular degenerative, neurodegenerative, autoimmune, developmental, traumatic brain injury, concussion, hearing loss, metabolic diseases, and associated syndromes like spinal muscular atrophy, Alzheimer's, Parkinson's, and multiple sclerosis. The compositions comprise one or more isomers of dinitrophenol (DNP), such as 2,3-DNP, 2,4-DNP, 2,5-DNP, 2,6-DNP, 3,4-DNP, or 3,5-DNP; as well as a variety of DNP prodrugs, including amino acid esters, phosphate analogs, 1,3-diketo analogs, benzoate analogs, Gemini prodrugs, bioprecursor molecules, and combinations thereof.
The core problem addressed is the absence of effective, disease-modifying therapies for conditions such as neurodegenerative, neuromuscular, developmental, autoimmune, and metabolic diseases, where current drug therapies are limited to palliative care or symptom management without altering disease progression or improving lifespan. The invention specifically targets unmet needs in diseases like ALS, Alzheimer's, multiple sclerosis, muscular dystrophies, developmental diseases (e.g., Rett and Angelman syndromes), and metabolic diseases such as obesity and its complications.
The invention introduces DNP-based compounds and prodrugs designed to provide disease-modifying effects, with particular emphasis on formulations that improve pharmacokinetic profiles, bioavailability, and safety. Prodrugs are chemically or enzymatically processed in vivo to release active DNP, enabling sustained therapeutic concentrations at reduced toxicity. The invention also covers various dose forms, release profiles, and delivery methods, including depot nanoparticle formulations, oral, intravenous, and transdermal routes, ensuring flexibility for patient-specific needs.
Claims Coverage
There are two independent claims in the patent, each introducing a distinct inventive feature focused on the method of treating multiple sclerosis (MS), traumatic brain injury (TBI), and Parkinson's disease with a specific class of DNP prodrugs.
Treatment of MS, TBI, and Parkinson's disease with dinitrophenol prodrug of formula II at specified dosage range
A method comprising administering to a patient in need of treatment a dose of a composition comprising a dinitrophenol prodrug of formula II. - The formula II prodrug is administered at a dosage of: - About 0.01 mg/kg of body weight to about 25 mg/kg of body weight, or - About 0.01 mg/kg of body weight to about 50 mg/kg of body weight of the patient. This inventive feature explicitly covers the specified prodrug structure and the defined dosage range for treating MS, TBI, and Parkinson’s disease.
Treatment of MS, TBI, and Parkinson's disease with dinitrophenol prodrug of formula II at alternate dosage range based on standard body weight
A method comprising administering to a patient in need of treatment a dose of a composition comprising a dinitrophenol prodrug of formula II. - The formula II prodrug is administered at a dosage of: - About 1 mg/70 kg of body weight to about 200 mg/70 kg of body weight of the patient. This inventive feature also explicitly covers the same prodrug but with a different dosage range based on a standard patient body weight. Both inventive features are directed at the use of a defined DNP prodrug (formula II) for treating MS, TBI, and Parkinson’s disease across specified dosing regimens.
The independent claims establish method-of-treatment coverage for administering defined dosages of a dinitrophenol prodrug (formula II) to patients with multiple sclerosis, traumatic brain injury, and Parkinson's disease, specifying both per kg and per 70 kg body weight dosage ranges.
Stated Advantages
DNP prodrugs offer sustained release, enabling prolonged therapeutic exposure and improved pharmacokinetic profiles compared to parent DNP.
The prodrug approach allows for lower peak plasma concentrations and reduces the risk of acute adverse effects traditionally associated with DNP.
DNP prodrugs demonstrate stability in the gastrointestinal tract and controlled hydrolysis in plasma, enhancing systemic bioavailability and safety.
The invention provides a disease-modifying approach to conditions for which current therapies are only palliative or non-modifying.
Depot nanoparticle and extended release formulations improve dosing convenience and patient compliance, allowing less frequent administration.
Formulations overcome limitations of poor water solubility and unfavorable pharmacokinetics of DNP, providing tailored drug release.
Demonstrated efficacy in animal models for lowering or blocking disease progression (e.g., paralysis in MS model) and preserving body weight.
Documented Applications
Treatment of multiple sclerosis (MS), including relapse-remitting, secondary-progressive, primary-progressive, and progressive-relapsing subtypes.
Treatment of traumatic brain injury (TBI) and concussion.
Treatment of Parkinson's disease, including idiopathic, vascular, dementia with Lewy bodies, inherited, drug-induced parkinsonism, juvenile, and atypical forms.
Treatment of neuromuscular and neurodegenerative diseases including ALS, Alzheimer's disease, Huntington's disease, Spinocerebellar ataxias, Batten disease, and muscular dystrophies (e.g., Duchenne, Becker, Myotonic, Congenital, Emery-Dreifuss, Facioscapulohumeral, Limb-girdle, Distal, Oculopharyngeal).
Treatment of developmental and genetic disorders such as Rett syndrome, Angelman's syndrome, Prader Willi Syndrome, Fragile-X Syndrome, Leigh disease, Autism Spectrum Disorders.
Treatment of autoimmune diseases such as Sjögren's syndrome, rheumatoid arthritis, lupus, Graves' disease, Guillain-Barre syndrome, myasthenia gravis, and autoimmune CNS disorders.
Treatment of hearing loss due to aging, noise, drug-induced or genetic causes.
Treatment of metabolic diseases and related disorders, including obesity, Type-1 and Type-2 diabetes, MODY subtypes, metabolic syndrome, nonalcoholic steatohepatitis (NASH), and related complications.
Prevention or reduction of muscle wasting in neuromuscular and neurodegenerative contexts.
Treatment of cognitive disorders associated with neuromuscular diseases like Duchenne muscular dystrophy.
Treatment of dry eye disease (keratoconjunctivitis sicca), glaucoma, and post-LASIK surgery complications.
Treatment of Wolfram Syndrome and Wolcott-Rallison syndrome, including associated diabetes, hearing, vision, ataxia, and neurodegeneration.
Treatment of depressive disorders, schizophrenia, and other psychiatric or neuropsychological disorders as listed.
Treatment of burns and support in severe injury for mitigation of associated muscle and tissue degeneration.
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