MitoRx: AP39 Mitochondrial Donor Significantly Reduces Obesity

In OXFORD, United Kingdom, on October 10, 2024, MitoRx Therapeutics, a biotechnology company specializing in mitochondrial-targeted therapies for obesity-related disorders and myopathies, has made a significant announcement. Their recent study has been published in the acclaimed biomedical sciences journal, Pharmacological Research, by Elsevier. This research, conducted by Jagiellonian University Medical College, delves into the impact of MitoRx's proprietary mtH2SD compound, AP39, on obesity induced by a high-fat diet (HFD) in a preclinical mouse model.

The study marks the pioneering effort to investigate whether mitochondrial sulfide donors can combat weight gain and fatty liver, also known as steatosis. Hydrogen sulfide, a vital signaling molecule in the liver, plays a crucial role in regulating lipid metabolism and mitochondrial function. However, its direct delivery to mitochondria as a treatment for obesity-related metabolic disorders had not been explored until now.

The research, co-authored by MitoRx's Chief Scientific Officer Prof. Matt Whiteman, Senior Discovery Chemist Dr. Roberta Torregrossa, and Dr. Mark Wood from the University of Exeter, demonstrated remarkable results. AP39 was shown to reduce weight gain by 32% in mice on a high-fat diet by the study's conclusion.

AP39, a versatile mtH2SD tool compound, significantly reduced liver steatosis, triglycerides, de novo lipogenesis, and inflammatory markers. It also led to notable downregulation of liver proteomic markers associated with weight gain and obesity, suggesting that the mtH2SD mechanism alleviates obesity through the mTOR/SREBP-1/SCD1 pathway. MitoRx is advancing undisclosed next-generation mtH2SDs for clinical applications. This therapeutic strategy not only protects muscles, including in severe fibrotic muscle atrophy models, but also exhibits anti-obesogenic properties. Consequently, MitoRx's next-gen mtH2SDs have the potential to address both sarcopenic obesity and muscle wasting in obese individuals, a significant improvement over current GLP-1 receptor agonist drugs, which often lead to muscle loss.

Dr. Jon Rees, CEO of MitoRx, emphasized the company's progress in developing first-in-class mitochondriotropic platforms initially targeting myopathies, now extended to obesity. He highlighted that the recent publication provides solid preclinical evidence that AP39 considerably curbed weight gain in HFD-fed animals, suggesting a promising new pathway to mitigate obesity without the muscle-wasting side effects associated with GLP-1 receptor agonists. Dr. Rees praised the collaborative effort with Jagiellonian University's Faculty of Medicine, emphasizing its role in accelerating therapeutic advancements for patients.

Dr. Aneta Stachowicz, the lead author of the Pharmacological Research paper from Jagiellonian University Medical College, expressed optimism about the study's findings. She noted that demonstrating the effectiveness of mitochondrial-targeted sulfide donors in reducing weight gain and multiple obesity markers marks the beginning of a novel therapeutic approach for metabolic diseases through mitochondrial sulfide-signalling modulation.

Prof. Matt Whiteman from the University of Exeter Medical School, a co-author of the study, highlighted the historical context of their research. In 2010, they identified impaired sulfide metabolism in overweight type 2 diabetes patients, driven by excess fat tissue. This observation, now confirmed by numerous studies, suggested that addressing this impairment with mtH2SD could potentially treat diabetes, obesity, and related complications. Prof. Whiteman expressed satisfaction in translating these findings into clinically viable drugs with MitoRx's collaboration.

The study’s results are groundbreaking for the development of innovative therapies targeting mitochondrial functions to combat obesity and related metabolic disorders. This research opens new avenues for therapeutic strategies, potentially benefiting millions of individuals struggling with obesity and its associated health issues.