作者: Sullivan, Patrick G ; Geisler, John G ; Brown, Emily ; Prajapati, Paresh ; Hubbard, W Brad ; Kalimon, Olivia J ; Velmurugan, Gopal V ; Vekaria, Hemendra J

Mild traumatic brain injury (mTBI) results in impairment of brain metabolism, which is propagated by mitochondrial dysfunction in the brain. Mitochondrial dysfunction has been identified as a pathobiological therapeutic target to quell cellular dyshomeostasis. Further, therapeutic approaches targeting mitochondrial impairments, such as mild mitochondrial uncoupling, have been shown to alleviate behavioral alterations after TBI. To examine how mild mitochondrial uncoupling modulates acute mitochondrial outcomes in a military-relevant model of mTBI, we utilized repeated blast overpressure of 11 psi peak overpressure to model repeated mild blast traumatic brain injury (rmbTBI) in rats followed by assessment of mitochondrial respiration and mitochondrial-related oxidative damage at 2 days post-rmbTBI. Treatment groups were administered 8 or 80 mg/kg MP201, a prodrug of 2,4 dinitrophenol (DNP) that displays improved pharmacokinetics compared with its metabolized form. Synaptic and glia-enriched mitochondria were isolated using fractionated a mitochondrial magnetic separation technique. There was a consistent physiological response, decreased heart rate, following mbTBI among experimental groups. Although there was a lack of injury effect in mitochondrial respiration of glia-enriched mitochondria, there were impairments in mitochondrial respiration in synaptic mitochondria isolated from the prefrontal cortex (PFC) and the amygdala/entorhinal/piriform cortex (AEP) region. Impairments in synaptic mitochondrial respiration were rescued by oral 80 mg/kg MP201 treatment after rmbTBI, which may be facilitated by increases in complex II and complex IV activity. Mitochondrial oxidative damage in glia-enriched mitochondria was increased in the PFC and hippocampus after rmbTBI. MP201 treatment alleviated elevated glia-enriched mitochondrial oxidative damage following rmbTBI. However, there was a lack of injury-associated differences in oxidative damage in synaptic mitochondria. Overall, our report demonstrates that rmbTBI results in mitochondrial impairment diffusely throughout the brain and mild mitochondrial uncoupling can restore mitochondrial bioenergetics and oxidative balance.

2020-01-01·Neurobiology of Aging2区 · 医学

A mitochondrial uncoupler prodrug protects dopaminergic neurons and improves functional outcome in a mouse model of Parkinson’s disease

2区 · 医学

Article

作者: Joshua Johnson ; Joshua Halpern ; William Fang ; John G. Geisler ; Krisztina Marosi ; Mark P. Mattson ; Yuki Kishimoto ; Dong Liu

Dopaminergic neuronal cell loss in the substantia nigra is responsible for the motor symptoms that are the clinical hallmark of Parkinson's disease (PD). As of yet there are no treatments that slow or prevent the degeneration of dopaminergic neurons in PD patients. Here we tested the hypothesis that dopaminergic neurons can be protected by treatment with the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) and the novel DNP prodrug MP201. We found that mice treated with low doses of DNP and MP201 were protected against motor dysfunction and dopamine neuron loss in the 6-hydroxydopamine PD model, with MP201 being more efficacious than DNP. Amelioration of motor deficits and dopamine neuron loss by MP201 treatment was associated with reductions in microglial and astrocyte activation and neuroinflammation. These preclinical findings suggest the potential application of mitochondrial uncoupling agents such as MP201 as disease-modifying therapies for PD.

2019-12-01·Neurochemistry International3区 · 医学

Disease modifying mitochondrial uncouplers, MP101, and a slow release ProDrug, MP201, in models of Multiple Sclerosis

3区 · 医学

Article

作者: Yoshio Bando ; John G. Geisler

Mitochondrial dysfunction is thought to be involved in the pathogenesis of MS and here we tested if brain penetrant mitochondrial uncouplers, DNP (MP101) and a novel prodrug of DNP (MP201), have the pharmacology to suppress demyelination and axonal loss in two independent models of MS by modulating the entire organelle's physiology. First, the gold standard EAE mouse model for MS was evaluated by daily oral treatment Day 7-21 with either MP101 or MP201 post-immunization. Both MP101/MP201 significantly suppressed progression of paralysis with limited infiltration of inflammatory cells. Strikingly, although mitochondrial uncouplers do increase energy expenditure even at the low doses provided here, they paradoxically preserved body weight at all doses in comparison to wasting in advanced paralysis of the placebos. Second, the effects of the compounds on suppressing inflammation were also evaluated in the cuprizone model, independent of the immune system. MP101/MP201 had a striking effect preserving both myelination and protecting the axons, in comparison to the placebos where both were destroyed. Both MP101/MP201 induced a significant and sustained increase in neurotrophin, BDNF, in the spinal cords. Both MP101/MP201 suppressed the expression of inflammatory cytokines including IL-1β, TNF-α and iNOS. Results indicate that MP101/MP201 may be a "disease modifying" treatment for MS by specifically modulating mitochondrial physiology. This would be a completely novel treatment for MS, targeting the mitochondria directly using a unique platform, mitochondrial uncouplers, that initially act non-genomically based upon biophysics, but cascades into cellular remodeling, neuroprotection and pro-survival. Clinical Phase I testing of MP101 in Normal Healthy Volunteers (NHV) is currently underway allowing for the potential to subsequently evaluate translation in MS patients and other insidious diseases, at expected weight neutral doses.

项与 MP-201 相关的新闻（医药）

2024-01-10

·Pharmaceutical Technology

EMA approves Mitochon’s neurogenerative disease study

Mitochon’s small molecule candidate MP101 modulates mitochondrial function to treat neurogenerative diseases. Credit: Solskin via Getty Images. The European Medicines Agency (EMA) has awarded approval to Mitochon Pharmaceuticals to initiate a Phase I/IIa biomarker study to treat patients with several neurogenerative diseases. The 14-day pilot study will investigate MP101, a small molecule orally administered drug which targets mitochondrial function. The clinical trial will enrol patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis, Huntington’s disease, and Alzheimer’s disease, and evaluate the safety and potential changes in disease-specific biomarkers of the drug. Mitochon received orphan drug designation from the US Food and Drug Administration (FDA) for MP101 to treat Huntington’s disease and ALS, in 2019 and 2020, respectively. The candidate generated promising results in preclinical studies, with Mitochon reporting that MP101 indicated favourable pharmacological and biochemical responses. Data showed that MP-101 preserves brain volume, medium spiny neurons, general neurons and limb movement, as well as reducing seizure duration. According to GlobalData’s Pharma Intelligence Center, MP101 has been investigated in several clinical studies, including for optic neuritis, in normal healthy volunteers, and in Huntington’s disease patients. GlobalData is the parent company of Pharmaceutical Technology. In the announcement accompanying the approval, Mitochon’s co-founder and chief scientific officer (CSO) John Geisler said: “We are delighted for the opportunity to explore this provocative idea that most, if not all neurodegenerative diseases are rooted in mitochondrial dysfunction. We predict that chronic treatment with this unique platform, at micro-doses, will resolve mitochondrial issues and change important disease-specific biomarkers in all four indications similarly.” According to GlobalData’s Pharma Intelligence Center, Mitochon has another drug in its pipeline, MP201. The therapy modulates mitochondrial function, protecting the neurons through mitochondrial uncoupling, which prevents excessive ROS formation and oxidative damage. The candidate is also under development for the treatment of Parkinson’s disease, amyotrophic lateral sclerosis, and traumatic brain injury. In July 2023, InSilicoTrials and Axoltis teamed up to develop disease-modifying drugs for neurological disorders. Precision Biosciences filed a patent in September 2023 on a mitochondria-targeting engineered meganuclease for modifying human mitochondrial DNA.

孤儿药

2024-01-09

·Business Wire

European Medicines Agency (EMA) Greenlights Mitochon Pharmaceuticals to Initiate Phase I/IIa Biomarker Study in Neurodegenerative Diseases

BLUE BELL, Pa.--( BUSINESS WIRE )-- Mitochon Pharmaceuticals today announced that it was awarded approval from EMA to begin enrollment for a Phase I/IIa biomarker study in Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Huntington’s Disease (HD) and Alzheimer’s Disease (AD) participants. Mitochon’s MP101, a once-daily, oral brain penetrant mitochondrial stimulator, that improves central nervous system survival and function will be used in this 14-day pilot study. The aim of the study is to show safety in the target patient populations and demonstrate meaningful changes in disease specific biomarkers. Successful completion of this study will provide the basis for long term Phase IIb clinical studies in ALS, Secondary & Primary Progressive MS, HD, and AD patients, leading to the first mitochondrial specific therapy for these truly insidious diseases. “We are delighted for the opportunity to explore this provocative idea that most, if not all neurodegenerative diseases are rooted in mitochondrial dysfunction. We predict that chronic treatment with this unique platform, at micro-doses, will resolve mitochondrial issues and change important disease specific biomarkers in all four indications similarly,” said Dr. John G. Geisler, Ph.D., co-founder and CSO of Mitochon. MP101 and MP201 are mitochondrial targeted, once-a-day, oral therapies that have been shown to shield cells from damage caused by a host of degenerative processes (genetic and non-genetic, auto-immune and injury). In preclinical studies, these compounds have exhibited striking protective and functional benefits in disease models. Benefits include: brain volume sparing in Huntington’s disease; axonal protection from demyelination in Multiple Sclerosis, protection of neuromuscular junction in ALS, blocking the loss of short-term memory in Alzheimer’s, and protecting brain cells from traumatic brain injury (TBI) such as severe concussions. About Mitochon Pharmaceuticals Mitochon was founded in 2015 with the mission to develop treatments for insidious diseases through the modulation of mitochondrial physiology, with applications to neurodegeneration, neuromuscular, and neuro-trauma. Mitochon’s lead programs, MP101 and MP201, specifically harnesses the power of the mitochondria to provide broad neural protection (MOA: https://www.mitochonpharma.com/mechanism-of-action/ ). These compounds elicit mild increases in energy expenditure that result in strengthening cellular survival – similar to the positive effects seen with fasting and exercise. These compounds also induce an important neurotrophin, Brain Derived Neurotrophic Factor (BDNF), involved in cognition, growth and repair. Additional Information: www.mitochonpharma.com

临床2期

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适应症	最高研发状态	国家/地区	公司	日期
创伤性脑损伤	临床1期	美国	Mitochon Pharmaceuticals, Inc.初创企业	2020-06-06
帕金森病	临床1期	美国	Mitochon Pharmaceuticals, Inc.初创企业	2017-11-07
视神经炎	药物发现	美国	Mitochon Pharmaceuticals, Inc.初创企业	2020-06-25