Selectively Modulating Adult Stem Cells to Treat Muscle Wasting Diseases

Funding Type: 
Early Translational II
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

The scientific advancements of stem cell and developmental biology over the last decade have formed a solid foundation to pursue regenerative medicines for diseases with little to no treatment options. These discoveries have contributed to a more comprehensive understanding of stem cell niches across many tissues of the body and of the key stem cell pathways, such as Wnt, Hedgehog and Notch, which can be specific to and influence these niches. The quickest way to bring in the horizon for stem cell medicines may be through the use of conventional pharmaceuticals to modulate key stem cell pathways. The premise of this approach is to intervene using small molecules and biologics, modulating stem cell biology for a desired outcome such as cell proliferation and differentiation for therapeutic benefit. As each year passes, more stem and progenitor cell populations are being identified in adult tissues, and myriad proof of concepts for treating diseases have emerged based on activating stem and progenitor cells.

The goal of this project is to identify new small molecule or protein therapeutics that can attenuate, prevent, or reverse muscle-wasting in patients by stimulating the endogenous regenerative capacity of skeletal muscle. Muscle-wasting disorders are a large and growing public health problem affecting more than 22 million people in the U.S. Skeletal muscle contains a defined population of adult stem cells, called satellite cells, which are important for muscle’s natural growth and repair. However, until recently, no single marker or mechanism of action was known and could provide a therapeutic opportunity into this process. Today, we can identify a subset of satellite cells that is capable of self-renewal and long-term reconstitution of the satellite cell niche necessary for proper muscle maintenance. Our research has also elucidated the important mechanism by which the satellite stem cells proliferate to facilitate normal muscle regeneration. This proliferation is mediated by a Wnt7a, which is specific to skeletal muscle and is an important point for new therapeutic intervention for muscle-wasting diseases. We propose to translate this basic science research breakthrough into a development candidate through our specific ability to query this biology and screen for small molecule activators of this pathway. To recapitulate human physiology and improve drug screening results, we will use primary human satellite stem cells as well as employ advanced induced pluripotent stem cell (iPSC) technology to support secondary screening. Overall this proposed research leverages the most advanced stem cell research and technology to bring forward a developmental drug candidate to address muscle-wasting diseases, a devastating and growing health problem facing California and our nation.

Statement of Benefit to California: 

Muscle-wasting syndromes such as disuse atrophy, cachexia, and sarcopenia affect millions of patients and represent significant areas of unmet medical need. More than 17 million people in the U.S., including 1.8 million in California, suffer from sarcopenia, which is considered by the Centers for Disease Control as one of the top five major U.S. health risks. Approximately, 45 percent of the elderly U.S. population is sarcopenic. These disorders, as diseases of aging, are a major cause of quality of life problems and increased healthcare costs. Sarcopenia affects all elderly regardless of ethnicity, gender or wealth. Elderly patients suffering from sarcopenia often require assistance to accomplish basic tasks of independent living and are also at increased risk of serious injury from falls and fractures. For 2007, U.S. healthcare costs directly attributed to sarcopenia exceeded $26 billion, of which California spent more than $3 billion to treat and manage this debilitating disorder. With an aging demographic, we can expect this health problem to only continue to grow and the demands on healthcare systems to increase. The ability to positively affect just 10 percent of the sarcopenic patients with a new therapeutic would result in healthcare savings of more than $3 billion as well as restore quality of life for these patients.

Current treatments rely on steroids or steroidal mechanisms of actions, but no approved therapies exist today that can reverse the effects of muscle wasting to improve the function and mobility of sufferers. Our research has identified a method to specifically activate satellite stem cells to proliferate, thereby increasing the underlying stem cell population and restoring muscle mass. This breakthrough creates a new paradigm in satellite stem cell biology that can be leveraged for therapeutic intervention. The elucidation and therapeutic targeting of other stem cell mechanisms, such as bone morphogenic proteins and erythropoietin in bone and blood, have created new medicines addressing billion dollar markets. This proposal would provide the necessary translational research to identify a drug candidate that could be a first-in-class therapeutic capable of specifically targeting the relevant pathways leading to satellite stem cell expansion, thereby stimulating the endogenous regenerative capacity of skeletal muscle. There is clearly a profound need to address muscle-wasting disorders, including sarcopenia, for the sufferers of this disease as well as to alleviate the already overburdened healthcare system. This proposed research leverages breakthroughs in stem cell research to accelerate the development of much needed new medicines not only for citizens of California but for the nation and world. Furthering this promising discovery to establish a drug candidate for sarcopenia will help address this growing public health problem that currently has no solution.