miR-22

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.

TORINO, Italy--(BUSINESS WIRE)-- Resalis Therapeutics today announced the closing of a €10 million ($11 million) Series A financing round led by Sunstone Life Science Ventures with participation from existing investors including Claris Ventures and angel investors. The proceeds will be used to initiate and complete the first-in-human Phase 1 clinical trial and reach Phase 2 readiness for Resalis’ lead program, RES-010, in obesity. RES-010 is a non-coding RNA-based compound designed to provide a disease-modifying approach in obesity with longer-lasting weight reduction and the ability to extend treatment durability in combination with approved therapeutics, such as GLP-1 receptor agonists. In conjunction with the financing, Claus Andersson, PhD, General Partner of Sunstone Life Science Ventures, will join Resalis’ Board of Directors. “The successful close of our Series A is an important milestone for Resalis because it will enable us to reach the clinic and to achieve the next significant inflection point with our lead candidate, RES-010. With RES-010 we aim to provide a therapeutic that precisely reduces fat mass in obesity with the potential to extend the durability of existing therapies. We value the trust and support of our new and current investors, and eagerly look forward to this next phase of development,” said Alessandro Toniolo, CEO of Resalis Therapeutics. “Resalis’ therapeutic approach is based on groundbreaking science that has rapidly led to the development of a lead candidate, now on the cusp of clinical evaluation. Preserving muscle mass is key to provide a sustained and meaningful clinical benefit, and we share the team’s vision that this non-GLP1/GIP therapeutic will significantly improve both effect and tolerability of today’s therapies. This investment underscores our belief in the company’s vision and the transformative potential of its lead candidate to make a meaningful impact for obese patients,” said Claus Andersson, General Partner at Sunstone Life Science Ventures. Pietro Puglisi, Managing Partner at Claris Ventures and Chairman of the Board at Resalis Therapeutics, added: “In recent years, there has been remarkable progress in the treatment of metabolic disorders. Yet, there persists a critical need for innovative solutions that can both provide orthogonal therapeutic effects and pave the way for combination therapies. I look forward to the continued collaboration with the outstanding Resalis team and welcoming Claus as a new member of the Resalis Board.” Resalis has a deep understanding of the field of ncRNAs and RNA-targeted therapeutics in human health and metabolic disorders. The company’s lead candidate, RES-010, is an antisense oligonucleotide that targets miR-22, a central player in the regulation of lipid metabolism and energy consumption. In multiple proof-of-concept studies in large and small animal models, RES-010 has shown the potential to provide a safe and longer-lasting therapeutic effect, alone or in combination with approved drugs. Resalis plans to initiate a Phase 1 clinical study evaluating the safety and efficacy of RES-010 in the first half of 2024. RES-010 is patent-protected in the US, Japan and China with patents pending in the EU. About Resalis Therapeutics Resalis Therapeutics’ transformative metabolic disease approach targets a master regulator of multiple pathways underlying obesity and fatty liver disease. The company is applying its profound understanding of the non-coding RNA drug modality and lipid metabolism to develop its lead program, RES-010, into a safe and convenient treatment providing disease-modifying therapeutic impact including durable weight loss and reduction of hepatic steatosis. Building on robust preclinical evidence, Resalis will rapidly bring RES-010 into clinical trials for a range of metabolic disorders. For more information visit our website . About Sunstone Life Science Ventures Sunstone Life Science Ventures is an independent European venture capital investment firm founded in 2007 by an international team of industry experts with combined entrepreneurial, operational and financial experience. Managing total funds of €300 million, Sunstone focuses on developing and expanding early-stage Life Science companies with strong potential to achieve global success in their markets. Since inception, Sunstone has invested in more than 60 companies, and has completed more than 25 successful IPOs and large M&A transactions. About Claris Ventures Claris Ventures SGR is a venture capital firm based in Italy, founded in 2019. Its first fund under management, Claris Biotech I, is focused on early-stage investments in high potential biopharma companies arisen from the Italian R&D ecosystem – both local and international. The firm identifies and supports innovation in the pharmaceutical space, investing in new companies with transformational drugs under development. It aims at the highest impact possible on highly unmet patients need, building value around strong science. Claris Ventures SGR pursuit for high potential projects involves every research center, clinical structure and company in the Italian life sciences network, whether the founding team is based in Italy or it includes Italian scientists abroad who have strong links with Italy. View source version on businesswire.com: Contacts Contact Resalis Alessandro Toniolo, CEO +393386092544 alessandro.toniolo@resalistherapeutics.com Media Relations Trophic Communications Gretchen Schweitzer or Charlotte Spitz Trophic Communications +49 171 351 2733 resalis@trophic.eu Source: Resalis Therapeutics View this news release online at:

Gene therapy with microRNA-22 produced better survival outcomes than the current FDA-approved drug for liver cancer and without noticeable toxicity in new mouse study. Gene therapy that induces the body to create microRNA-22 (miR-22), a naturally occurring molecule, successfully treated mice with hepatocellular carcinoma, the most common form of liver cancer. The miR-22 treatment also reduced liver inflammation and produced better survival outcomes with no observable toxicity compared to the FDA-approved liver cancer treatment lenvatinib. Those are the findings of a new study from the UC Davis Comprehensive Cancer Center published in Molecular Therapy. "This research introduces miR-22 gene therapy as a promising and innovative approach for treating hepatocellular carcinoma," said Yu-Jui Yvonne Wan, senior author of the study. Wan is a distinguished professor and vice chair for research in the UC Davis Department of Pathology and Laboratory Medicine. "The study's findings suggest that miR-22 therapy could provide better survival outcomes, enhance anti-tumor immunity, improve metabolism and reduce inflammation." The University of California filed a patent application for Wan's discovery of miR-22 for treating hepatic and metabolic diseases. The patent is currently pending. MicroRNAs' role in health and disease MicroRNAs are small molecules that contain ribonucleic acid (RNA), a type of genetic material. MicroRNAs are widely found in plants and animals. They are "non-coding," meaning they do not make proteins like some other RNA molecules. In the case of miR-22, it acts like a brake, stopping the production of certain proteins, including cyclin A, protein deacetylases and hypoxia-inducible factor, that can fuel liver cancer growth. A lack of miR-22 is found in hepatocellular carcinoma tumors, and its levels can predict survival time for patients with the disease. Wan studies the interaction between gut microbes and the liver, what's known as the gut-liver axis. Her previous research shows that metabolites produced by the gut microbiome help create miR-22 and have anti-cancer benefits. These metabolites include retinoic acid, short-chain fatty acids, bile acids and vitamin D3. When people have colon or liver cancer, signaling from these metabolites is reduced, which in turn reduces miR-22. This was a clue for Wan that returning miR-22 to a higher level might act as a treatment for liver cancer. She launched several studies, including one demonstrating miR-22 could suppress liver tumors by targeting both liver and immune cells. Gene therapy to test efficacy of miR-22 for liver cancer For this study, Wan and first author Ying Hu, an assistant professional researcher in Wan's lab, turned to gene therapy. Using an inactivated adenovirus, they introduced miR-22 into the mice with a single intravenous injection. The mice treated with the gene therapy were compared with mice treated with the current FDA-approved drug lenvatinib (administered orally once a day), untreated mice and healthy mice. Both miR-22 and lenvatinib inhibited the progression of the liver cancer compared to untreated mice. However, the miR-22-treated mice had longer survival times without toxicity compared with lenvatinib-treated mice. Some of the study's key findings: Liver cancer is a leading cause of death worldwide According to the American Cancer Society, liver cancer is a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths each year.In the United States, each year about25,000 men and 11,000 women are diagnosed with liver cancer, while 19,000 men and 9,000 women die from the disease. Risk factors for liver cancer include long-term hepatitis B or hepatitis C infections, obesity, non-alcoholic fatty liver disease, excess alcohol consumption, auto-immune liver disease and exposure to aflatoxins (a toxin found in moldy peanuts or grains). Hepatocellular carcinoma is becoming a bigger problem due to rising obesity rates worldwide, including in the U.S. Drugs to treat hepatocellular carcinoma -- sorafenib, lenvatinib, regorafenib, and cabozantinib -- are associated with considerable toxicities and poor quality-of-life outcomes. The survival benefit is limited to a few months and the cost is very high. "The positive findings from this preclinical study give us hope that miR-22 could be a promising alternative to treat hepatocellular carcinoma," Hu said. Additional authors include Tahereh Setayesh, Farzam Vaziri, Xuesong Wu and Samuel T. Hwang from the University of California, Davis.