Induced expression of brain derived neurotrophic factor (BDNF) for treatment of neuromuscular, neurodegenerative, autoimmune, developmental and/or metabolic diseases
Inventors
Alonso, Robert • Geisler, John Gerard
Assignees
Publication Number
US-10864173-B2
Publication Date
2020-12-15
Expiration Date
2036-01-21
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Abstract
A method of treating a host of neuromuscular, neurodegenerative, developmental, autoimmune and metabolic diseases/disorders related to aging, such as traumatic injury, stroke, Huntington's disease, Epilepsy, Multiple Sclerosis (MS), Lupus, Type-1 and Type-2 diabetes, Maturity Onset Diabetes of the Young (MODY), myasthenia gravis (MG), rheumatoid arthritis (RA), Graves' disease, Guillain-Barré syndrome (GBS), metabolic syndrome, Muscular Dystrophy or Duchenne Muscular Dystrophy (DMD), severe burns, aging, Amyotrophic Lateral Sclerosis (ALS), Friedreich's Ataxia, Batten Disease, Alzheimer's disease, optic neuritis, Leber's hereditary optic neuropathy (LHON), autism, Rett syndrome, Batten Disease, Angelman's Syndrome, Leigh disease, Fragile-X Syndrome, depression, Parkinson's disease, mitochondrial diseases, developmental disorders, metabolic disease disorders and/or autoimmune disorders by inducing endogenous BDNF expression with DNP treatment to protect from neuromuscular dysfunction/disorders and/or neurodegeneration and/or muscle wasting. DNP was administered to mice daily over a range of doses, and subsequently BDNF expression in the brain showed a dose dependent and non-linear increase in expression.
Core Innovation
The invention provides pharmaceutical compositions and methods for treating neuromuscular, neurodegenerative, autoimmune, developmental, and metabolic diseases or disorders, as well as traumatic central nervous system (CNS) injuries, by administering 2,4-dinitrophenol (DNP) or its pharmaceutically acceptable salt, solvate, or hydrate. The compositions are formulated to deliver an effective dose of DNP, which is defined within a specific range (0.01–5 mg/kg) to induce endogenous expression of brain-derived neurotrophic factor (BDNF) and provide protection from neuromuscular dysfunction, neurodegeneration, and muscle wasting.
The problem addressed is the inadequate methods for inducing expression of endogenous BDNF, which plays a crucial role in neuronal development, neuroprotection, and as a myokine supporting muscle health. There exists a need for therapies that can effectively and safely increase BDNF levels, especially for a spectrum of diseases where BDNF transport or endogenous upregulation is needed but has not been satisfactorily achieved by previous approaches.
This invention discovers and utilizes the property of DNP, at defined dose ranges, to increase BDNF expression in a manner that is neither too high to be harmful nor too low to be ineffective. The methods include various release formulations (immediate, controlled, or sustained release) and unit doses adjusted for patient weight or absolute dosing, highlighting a non-linear, dose-dependent induction of BDNF with documented efficacy in animal models. This approach applies to a wide range of conditions, including but not limited to, Parkinson's disease, multiple sclerosis, spinal cord injury, Alzheimer's, epilepsy, Huntington's disease, Rett syndrome, and others as explicitly enumerated throughout the patent.
Claims Coverage
There are two independent claims in this patent, each defining a pharmaceutical composition with specific attributes for the treatment of a range of diseases or injuries.
Pharmaceutical composition of DNP for treating neuromuscular, autoimmune, neurodegenerative, developmental, or metabolic disease or traumatic CNS injury
A pharmaceutical composition comprising 2,4-dinitrophenol (DNP), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, formulated to deliver an effective dose of DNP in the range of 0.01 mg/kg to 5 mg/kg of body weight for treating neuromuscular, autoimmune, neurodegenerative, developmental, or metabolic diseases/disorders or traumatic CNS injury in a patient. The composition includes formulation options such as immediate release, controlled release, or sustained release.
Pharmaceutical composition of DNP with defined unit dose for treating neuromuscular, autoimmune, neurodegenerative, developmental, or metabolic disease or traumatic CNS injury
A pharmaceutical composition comprising 2,4-dinitrophenol (DNP), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and an effective unit dose of DNP in the range of about 0.1 mg to about 300 mg for treating neuromuscular, autoimmune, neurodegenerative, developmental, or metabolic diseases/disorders or traumatic CNS injury in a patient. The composition is provided in an immediate release, controlled release, or sustained release formulation.
The independent claims cover pharmaceutical compositions of DNP for the treatment of designated disease categories or injuries, specifying both weight-based and absolute unit dose ranges, and encompass various release formulations.
Stated Advantages
Allows safe and effective induction of endogenous BDNF expression for neuroprotection, neuromuscular support, and muscle protection.
Provides a non-invasive way to induce BDNF in both central and peripheral compartments, avoiding delivery challenges across the blood-brain barrier.
Employs dose ranges that avoid harmful or ineffective levels of BDNF induction, enabling titration for patient-specific needs.
Provides protective effects demonstrated by increased BDNF and functional improvements in animal models of multiple diseases, including lasting effects after dosing is stopped.
Documented Applications
Treatment of traumatic brain injury (TBI) and spinal cord injury.
Treatment of neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis (ALS).
Treatment of neuromuscular diseases such as muscular dystrophy and Duchenne muscular dystrophy (DMD).
Treatment of metabolic disorders including type 1 and type 2 diabetes, MODY, and metabolic syndrome.
Treatment of autoimmune diseases such as multiple sclerosis (MS), lupus, rheumatoid arthritis (RA), Graves' disease, and Guillain-Barré syndrome (GBS).
Treatment of developmental disorders including Rett syndrome, Fragile-X syndrome, Angelman's syndrome, Prader Willi Syndrome, and autism spectrum disorders.
Treatment of epilepsy and seizure disorders.
Treatment of mitochondrial diseases.
Treatment of depression and other psychiatric disorders including schizophrenia.
Treatment of aging-related neuromuscular or neurodegenerative disorders.
Treatment and prevention of muscle wasting.
Use for severe burns and in recovery from CNS injury.
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