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-10220006-B2
Publication Date
2019-03-05
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 (GB S), 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 a method of treating neuromuscular, neurodegenerative, developmental, autoimmune, and metabolic diseases or disorders related to aging by inducing endogenous expression of brain-derived neurotrophic factor (BDNF) through the administration of 2,4-dinitrophenol (DNP) within a specific dose range. The patent describes that DNP, as a mitochondrial uncoupler, stimulates increased expression of BDNF, which can protect against neuromuscular dysfunction and neurodegeneration, and prevent or reverse muscle wasting. Importantly, the invention identifies an optimal and non-linear dose range (from about 0.001 mg/kg to less than 10 mg/kg) where BDNF induction is maximized without being harmful to the patient.
The problem addressed is the need for improved methods to induce BDNF expression, as BDNF plays a key role in neuronal development, nerve growth, and muscle protection (as a neurotrophin and myokine). Prior to this invention, approaches focused on getting BDNF across the blood-brain barrier to treat a wide range of diseases, including traumatic injury, stroke, Huntington's disease, epilepsy, multiple sclerosis, lupus, diabetes, metabolic syndrome, muscular dystrophies, Alzheimer's disease, autism, depression, Parkinson's disease, and others. However, effective and safe induction of endogenous BDNF had not been established.
Through animal model experiments, the invention demonstrates that DNP administration in precise dosage increases BDNF at both the mRNA and protein level, resulting in meaningful benefits in models of multiple sclerosis, Rett syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, and epilepsy. The method relies on the mechanism of mitochondrial uncoupling leading to lower cellular stress, reduced reactive oxygen species, and activation of the cAMP-CREB pathway, which converts a non-genomic event into sustained genomic upregulation of BDNF. This chronic, controlled induction of BDNF shows protective and restorative effects in both central and peripheral tissues affected by these disorders.
Claims Coverage
There are three core inventive features found in the independent claims, focusing on methods of treating Parkinson's disease and multiple sclerosis with DNP using defined dosing regimens.
Method of treating Parkinson's disease with DNP at specified dose range
A method comprising administering to a patient in need of treatment a pharmaceutical composition of 2,4-dinitrophenol (DNP), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, with an effective dose of DNP in the range of 0.001 mg/kg of body weight to 5 mg/kg of body weight. This inventive feature is directly tied to the treatment of Parkinson's disease by precisely defined doses of DNP to induce therapeutic benefit.
Unit dose method of treating Parkinson's disease with DNP
A method comprising administering to a patient in need of treatment a pharmaceutical composition of 2,4-dinitrophenol (DNP), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, where the DNP is provided as a unit dose in the range of about 0.1 mg to about 300 mg. This inventive feature covers the administration of DNP for Parkinson’s disease as a single unit dose in a broad, specified range.
Method of treating multiple sclerosis with DNP at specified dose range and unit dose
A method comprising administering to a patient in need of treatment a pharmaceutical composition of 2,4-dinitrophenol (DNP), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, with an effective dose of DNP in the range of 0.001 mg/kg of body weight to 5 mg/kg of body weight. Also, providing the same therapy using a unit dose in the range of about 0.1 mg to about 300 mg. This inventive feature specifically addresses treatment of multiple sclerosis (including its clinical subtypes) using DNP either as a weight-adjusted dose or as a unit dose.
The claims focus on the therapeutic use of DNP, with precisely defined dosing regimens, for the treatment of Parkinson's disease and multiple sclerosis, covering both weight-adjusted and unit dose formulations.
Stated Advantages
Provides a method to induce endogenous BDNF expression in a dose-dependent and controlled manner, which avoids harmful overdose and ineffectiveness of underdose.
Attenuates disease progression and can provide remission or relief of symptoms in neuromuscular, neurodegenerative, developmental, autoimmune, and metabolic disorders by increasing BDNF.
The effect of DNP treatment on BDNF elevation is sustained for up to several weeks after cessation, potentially reducing dosing frequency.
Shows protection from neuromuscular dysfunction, neurodegeneration, and muscle wasting as demonstrated in various animal models.
Documented Applications
Treatment of Parkinson's disease by administration of DNP within specified dosing parameters.
Treatment of multiple sclerosis, including relapse-remitting, secondary-progressive, primary-progressive, and progressive-relapsing forms, by administration of DNP within specified dosing parameters.
Treatment or amelioration of Huntington's disease, Rett syndrome, Alzheimer's disease, epilepsy, traumatic brain injury, ischemic stroke, lupus, diabetes mellitus (Type-1, Type-2, MODY), metabolic syndrome, muscular dystrophies (including Duchenne), severe burns, aging-related disorders, amyotrophic lateral sclerosis (ALS), ataxias, Batten disease, optic neuritis, Leber's hereditary optic neuropathy (LHON), autism spectrum disorders, Angelman's syndrome, Leigh disease, Prader Willi syndrome, Fragile-X syndrome, depression, schizophrenia, rheumatoid arthritis, Graves' disease, Guillain-Barré syndrome, mitochondrial diseases, and other neuromuscular, neurodegenerative, developmental, metabolic, and autoimmune disorders by inducing BDNF expression through DNP treatment.
Prevention or reversal of neuromuscular dysfunction, neurodegeneration, and muscle wasting by administration of DNP to induce endogenous BDNF.
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