PGC-1α

While GLP-1 receptor agonists continue to post impressive weight loss data – and attract a slew of high-priced deals – the drugs face several shortcomings in obesity, including the duration of effect after treatment ends. Resalis is aiming to fill those holes with a complementary therapy: an antisense oligonucleotide (ASO) that targets miR-22, which controls multiple pathways associated with the metabolic root of obesity.The company raised €10 million in a series A Thursday that will enable the start and finish of a Phase I trial of its miR-22 targeting ASO, RES-010. The round, which comes a year after Resalis’ initial €10 million seed funding, was led by Sunstone Life Science Ventures with participation from existing investors including Claris Ventures and angel investors. One target, many pathwaysResalis’ strategy for a disease-modifying obesity therapeutic hinges on one microRNA (miRNA). Riccardo Panella began investigating miR-22 as a postdoc at Harvard Medical School and discovered its importance in multiple metabolic pathways – and its potential as a therapeutic target for obesity. Soon after, he started collaborating with Sakari Kauppinen to further explore the biology of miR-22, thanks to a grant from the Novo Nordisk Foundation, and they designed ASOs that could inhibit the target. After settling on a lead compound and amassing pharmacological and animal model data, the pair founded Resalis in 2021. Panella serves as chief scientific officer; Kauppinen is the company’s chief technology officer. “Because they’re very short, one miRNA can interact with a lot of different targets, depending on what is expressed at that moment in a cell or tissue,” Panella told FirstWord. Some of the key targets of miR-22 the Resalis team has identified include FGF21, ACLY, PGC-1α, and SIRT1 – all which have key roles in metabolic pathways.The ability to affect multiple targets is especially attractive in obesity because it’s a complex, multi-tissue, multi-pathway disease. With RES-010, “We found a way to hit multiple birds with one stone,” Panella said. “By silencing miR-22, we can deregulate multiple players at the same time that are important for driving the obesity phenotype.”Getting at the metabolic rootThe end goal is to rewire our cellular metabolism – making it harder for the body to store fat, and promoting energy consumption, Resalis CEO Alessandro Toniolo said. Mice data hints at what the result of such rewiring could look like in humans. In a study published last year in the International Journal of Molecular Sciences, Panella and Kauppinen found that when two groups of mice were fed high-fat diets, those with a miR-22 knockout gained significantly less weight than those with the target intact. Plus, another mice study showed that miR-22 inhibition only triggered fat loss, not muscle – another drawback to GLP-1 receptor agonism. Toniolo said the team found that, unless the mice had an excess of fat, they did not lose body weight. Because GLP-1 receptor agonists are appetite suppressors, patients often lose both fat and muscle mass, which can be unhealthy for the elderly. Another shortcoming facing the modality is that when patients stop taking the drugs, they often regain weight.However, Toniology believes pairing a GLP-1 receptor agonist with RES-010 for a course of treatment could resolve these issues. He doesn’t see the ASO replacing GLP-1s, but rather as a complementary therapy. Resalis plans to start a Phase I dose-ascending study of RES-010 in Europe this half.

Researchers have developed a novel screening method to identify a drug that mimics the effects of exercise on muscle and bone. Locamidazole (LAMZ) improved muscle width and function and promoted bone formation while reducing bone resorption. LAMZ serves as a potential therapy for the treatment of locomotor diseases, such as sarcopenia and osteoporosis. Maintaining a regular workout routine can help you look and feel great -- but did you know that exercise also helps maintain your muscles and bones? People who are unable to engage in physical activity experience weakening of the muscles and bones, a condition known as locomotor frailty. Recently, researchers in Japan have identified a new drug that may aid in the treatment of locomotor frailty by inducing similar effects as exercise. Physical inactivity can result in a weakening of the muscles (known as sarcopenia) and bones (known as osteoporosis). Exercise dispels this frailty, increasing muscle strength and promoting bone formation while suppressing bone resorption. However, exercise therapy cannot be applied to all clinical cases. Drug therapy may be helpful in treating sarcopenia and osteoporosis, especially when patients have cerebrovascular disease, dementia, or when they have already become bedridden. However, there is no single drug that addresses both tissues simultaneously. In a new study published in Bone Research, researchers from Tokyo Medical and Dental University(TMDU) developed a novel drug screening system to identify a compound that mimics the changes in muscle and bone that occur as a result of exercise. Using the screening system, the researchers identified the aminoindazole derivative locamidazole (LAMZ). LAMZ was capable of stimulating the growth of muscle cells and bone-forming cells, osteoblasts, while suppressing the growth of bone-resorbing cells, osteoclasts. When LAMZ was administrated to mice orally, it was successfully transmitted into the blood, with no obvious side effects. "We were pleased to find that LAMZ-treated mice exhibited larger muscle fiber width, greater maximal muscle strength, a higher rate of bone formation, and lower bone resorption activity," says lead author of the study Takehito Ono. The research team further addressed the mode of function of LAMZ and found that LAMZ mimics calcium and PGC-1α signaling pathways. These pathways are activated during exercise and stimulate expression of downstream molecules that are involved in the maintenance of muscle and bone. To investigate whether LAMZ can treat locomotor frailty, LAMZ was administrated to an animal model of sarcopenia and osteoporosis. "Both oral and subcutaneous administration of the drug improved the muscle and bone of mice with locomotor frailty," says senior author Tomoki Nakashima. Taken together, the research team's findings show that LAMZ represents a potential therapeutic method for the treatment of locomotor frailty by mimicking exercise.

Aug. 29, 2022 12:00 UTC -TQS-168 demonstrated robust geroprotective effects in preclinical studies- REDWOOD CITY, Calif.--(BUSINESS WIRE)-- Tranquis Therapeutics, Inc., a clinical stage immuno-neurology company developing innovative medicines with the potential to revolutionize the management of neurodegenerative and aging-related diseases, today announced it will present preclinical data on the anti-aging effects of TQS-168, a small molecule modulator of PGC-1a, at ARDD 2022, the 9th Aging Research and Drug Discovery meeting, taking place August 29 to September 2, 2022 at the University of Copenhagen, Denmark. In the preclinical study conducted in 18-month-old mice, it was shown that treatment for four months with TQS-168 resulted in a 66% improvement in the 31-point Frailty Index, a commonly used measurement to evaluate aging-related changes in mice. Treatment with TQS-168 also resulted in improvements in grip strength and treadmill running endurance, and a reduction in fat mass with no change in lean mass. These results indicate that TQS-168 has robust geroprotective effects in mice. TQS-168 was found to be well tolerated in healthy adult male subjects in a Phase 1 clinical trial. Adverse events were mild and transient, and no abnormalities were observed in laboratory parameters, ECG, or vital signs. No serious adverse events occurred. TQS-168 is ready for clinical trials to evaluate its potential to impact human aging and quality of life in the elderly. Tranquis is also advancing TQS-168 into clinical studies in other indications. About TQS-168 and PGC-1a TQS-168 is a PGC-1a-enhancing small molecule in development for the treatment of neurodegenerative, metabolic, and aging-related diseases in which PGC-1a modulation plays a critical role. PGC-1a is a transcriptional coactivator that regulates genes involved in cell energy metabolism, acting as a key regulator of mitochondrial biogenesis, giving TQS-168 potential as a target in a broad spectrum of diseases. TQS-168 showed survival and functional benefits in various animal models of neurodegenerative disease, including ALS and Parkinson’s disease. TQS-168 also demonstrated compelling biomarker data, including increased PGC-1a gene expression, reduction of inflammatory monocytes and cytokines, and reduced levels of neurofilament light in animal models. In vitro, TQS-168 also shows specific immunomodulatory effects in myeloid cell lines and in white blood cells from people living with ALS. About Tranquis Tranquis is a clinical-stage biopharmaceutical company developing a portfolio of small molecule therapeutics based on its unique approach of modulating PGC-1a to restore normal cell homeostasis and function. Tranquis’ platform has the potential to revolutionize the management of an entire range of indications in the fields of neurodegeneration, mitochondrial diseases, immuno-inflammation, and immunosenescence. In addition, the Company’s approach may promote healthy aging and longevity.