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A drug that boosts strength in injured or aging mice restores connections between nerves and muscle and suggests ways to combat weakness in humans due to aging, injury or disease. A small molecule previously shown to enhance strength in injured or old laboratory mice does so by restoring lost connections between nerves and muscle fibers, Stanford Medicine researchers have found. The molecule blocks the activity of an aging-associated enzyme, or gerozyme, called 15-PGDH that naturally increases in muscles as they age. The study showed that levels of the gerozyme increase in muscles after nerve damage and that it is prevalent in muscle fibers of people with neuromuscular diseases. The research is the first to show that damaged motor neurons -- nerves connecting the spinal cord to muscles -- can be induced to regenerate in response to a drug treatment and that lost strength and muscle mass can be at least partially regained. It suggests that, if similar results are seen in humans, the drug may one day be used to prevent muscle loss of muscle strength due to aging or disease or to hasten recovery from injury. It's estimated that sarcopenia, or debilitating muscle frailty, affects about 30% of people over 80 and costs the United States around $380 billion each year. "There is an urgent, unmet need for drug treatments that can increase muscle strength due to aging, injury or disease," said Helen Blau, PhD, professor of microbiology and immunology. "This is the first time a drug treatment has been shown to affect both muscle fibers and the motor neurons that stimulate them to contract in order to speed healing and restore strength and muscle mass. It's unique." Blau, the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology, is the senior author of the study, which was published online Oct. 11 in Science Translational Medicine. Postdoctoral scholar Mohsen Bakooshli, PhD, and former postdoctoral scholar Yu Xin Wang, PhD, are the lead authors of the study. Wang is now an assistant professor at the Sanford Burnham Prebys Medical Discovery Institute in San Diego. Addressing loss of strength The finding is the latest from the Blau laboratory focused on understanding how muscles weaken from aging or disease, and whether it's possible to combat this decline. In 2021, the group showed that blocking the activity of 15-PGDH in 24-month-old laboratory mice significantly enhances the animals' leg strength and endurance when running on a treadmill. (Laboratory mice typically live about 26 to 30 months.) But it wasn't clear exactly how. The new research shows that the effect is due to the restoration of lost connections between the nerves and the muscle. These connections, called neuromuscular junctions, are how the brain signals muscles to contract, allowing us to pick up a water glass, jog to the mailbox or hoist a toddler into a car seat. As we age, some of these connections are lost, causing muscle contractions to become less powerful and muscles to atrophy. People typically lose muscle mass and strength -- as much as 10% per decade -- after the age of 50. Conditions other than aging can also destabilize these connections, including the disuse of muscles due to bedrest after illness or injury, or muscle-wasting diseases like spinal muscular atrophy or amyotrophic lateral sclerosis (also known as ALS). Blau's previous research showed that a molecule called PGE2 is critical to the function of stem cells in muscle fibers that repair damage -- including the microtears from exercise that lead to an increase in muscle mass and strength. They subsequently showed that levels of 15-PGDH, which breaks down PGE2, increase in the muscles with age and that the loss of strength with aging could be overcome by inhibiting the activity of this PGE2-degrading enzyme. "PGE2 is part of the body's natural healing mechanism, and its levels increase in muscle after injury," Blau said. "We wanted to learn how age triggers an increase in 15-PGDH, and therefore the degradation and loss of PGE2." A lack of nerves The researchers knew that muscles become less innervated, or infiltrated with nerves, as people and animals age. They wondered if that loss could be what triggers the rising levels of 15-PGDH. "We found that when you cut the nerve that innervates the leg muscles of mice, the amount of 15-PGDH in the muscle increases rapidly and dramatically," Blau said. "This was an exciting new insight. But what surprised us most was that when these mice are treated with a drug that inhibits 15-PGDH activity, the nerve grows back and makes contact with the muscle more quickly than in control animals, and that this leads to a faster recovery of strength and function." Additional experiments showed that treatment with the drug restored neuromuscular junctions lost during aging and increased muscle strength and function in old laboratory mice. The researchers also identified discrete clumps of 15-PGDH in the muscle fibers of people with several types of neuromuscular disorders suggesting that the gerozyme may have a role in causing these human disorders. Blau and her colleagues plan to investigate at a molecular level how neural growth is stimulated by blocking 15-PGDH activity. Blau has also co-founded a company, Epirium Bio, to develop similar drugs for use in humans. Although her lab is still conducting animal studies, the company hopes to launch a clinical trial within the next year or so. "Our next steps will be to examine whether blocking 15-PGDH function in people with spinal muscular atrophy can increase lost muscle strength in combination with gene therapy or other treatments," Blau said. "We are also looking at ALS to see if something like this might help these patients. It's really exciting that we are able to affect both muscle function and motor neuron growth." The research was supported by the National Institutes of Health (grants K99NS120278, R00NS120278, R01-AG020961, R01-AG069858 and R01-RHG009674), the Canadian Institutes of Health, a Stanford Translational Research and Applied Medicine pilot grant, the Donald E. and Delia B. Baxter Foundation, the Li Ka Shing Foundation, the Milky Way Research Foundation and the California Institute for Regenerative Medicine. Blau is an inventor on several patents related to the research and a co-founder, consultant and equity holder of Epirium Bio, which has licensed patents regarding 15-PGDH inhibition to improve muscle strength.

The traditional way of drugging a protein is to get a small molecule to bind to it, but that’s not always feasible. Biotech startup Exo Therapeutics is developing a way to drug proteins by targeting places distant from a traditional binding site, and by doing so, affecting enzymes to produce a therapeutic effect. Cambridge, Massachusetts-based Exo has drug candidates that take this enzyme modulating approach to address cancer and inflammation and it has raised $78 million to support them as they advance toward clinical trials. The Series B round of funding announced Tuesday was led by Nextech Invest, a new investor in the company. The traditional binding places for small molecule drugs are called active sites. For some proteins, the active site is not available. Binding to another location on a protein called an allosteric site offers an alternative, but it could also have the unintended consequence of affecting other enzymes or blocking activity that you don’t want the drug to stop. Exo aims to hit locations on a protein called exosites. The company says that these binding pockets have the ability to reprogram enzyme activity to produce a therapeutic effect. Unlike active or allosteric sites, exosites are unique to a specific enzyme/substrate interaction. Exo claims that binding to them offers the potential of providing a better therapeutic window, fewer off-target effects, and fewer side effects. This approach also offers the potential to address many more diseases. Of the estimated 10,000 proteins involved in human disease, about 700 of them are currently accessible as drug targets. The company claims that targeting exosites will expand the universe of potential drug targets. The exosites are discovered using a technology called ExoSight. Exo’s research has produced a pipeline of four preclinical small molecules so far, three in oncology and one in inflammation. The company has not disclosed the specific targets of these drugs. In addition to supporting the ongoing development of its pipeline, Exo said that the new financing will be used to pursue new targets. The science of Exo’s approach is based on research from the Harvard University laboratory of David Liu, a professor of chemistry and chemical biology, and Alan Saghatelian, a professor at the Salk Institute for Biological Studies. Their work initially focused on insulin degrading enzyme (IDE), which degrades both insulin and glucagon. The scientists found that blocking the IDE exosite blocks the degradation of insulin but does not affect the protein’s active site or glucagon degradation. That research, which was published in 2019 in Nature Chemical Biology, led to the formation of Exo. The startup launched last December with $25 million in Series A funding. Other investors in Exo’s latest financing include BVF Partners, Samsara Biocapital, Morningside, Casdin Capital, Newpath Partners, Novartis Venture Fund, CRV, and 6 Dimensions Capital.

Novartis-backed Exo Therapeutics closed out 2020 by completing a $25 million Series A financing round. Nearly 10 months later, the small molecule drug discovery and development company has earned more support from investors. On Tuesday, Exo announced that it pulled in $78 million after completing an oversubscribed Series B round. The monies will be used to help the company pursue new targets with the ExoSightTM platform and to advance oncology and inflammation therapeutic candidates stemming from the platform into clinical trials. The financing round was led by Nextech Invest, which was joined by other new and existing investors including BVF Partners, L.P., Samsara Biocapital, Morningside and Casdin Capital, Newpath Partners, Novartis Venture Fund, CRV and 6 Dimensions Capital. Exo Therapeutics is based on research from David Liu, who has worked in CRISPR technologies and also ran a Harvard lab that developed a small molecule inhibitor of insulin-degrading enzymes. The company’s drug candidates bind exosites, which are binding pockets that reprogram enzyme activity for precise and robust therapeutic effect. “Exo is well positioned to capitalize on the tremendous opportunity that exosites represent,” said Michael Bruce, Ph.D., CEO of Exo Therapeutics. “With the support of our world-class investor syndicate and foundational work by professors David Liu and Alan Saghatelian, and their former student Juan Pablo Maianti, we are equipped to expand our ExoSight platform, discover new exosite targets and advance our initial programs towards the clinic.” Bruce, who has served as CEO of the Massachusetts-based company since early 2020, has more than 20 years of experience in drug discovery and development. Exo exited stealth mode in December 2020 with its Series A round and a dream of discovering and targeting the exosite on an enzyme. At the time of its launch, less than 700 enzymes made up the entire industry, with over 9,000 untouched. Bruce leads Exo with the belief that the company can create drugs to ‘drug the undruggable’ in areas such as cancer and inflammation. “Exo is at the forefront of integrated exosite science, aiming to unlock previously intractable drug targets,” Bruce said. “We look to leverage our team’s unmatched expertise and focus on drugging exosites as we advance towards proof-of concept drugs that we will progress to the clinic.”