Early Translational II
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.
This application for a Development Candidate Award focuses on identifying small molecule and protein therapeutics for muscle-wasting diseases, such as disuse atrophy, cachexia and sarcopenia. The applicant presents published and limited preliminary data identifying the protein Wnt7a and its downstream effectors as regulators of skeletal muscle satellite stem cell self renewal. In mice, this protein is capable of increasing satellite stem cell number and muscle mass. The applicant proposes to extend this work by evaluating systemic injection of Wnt7a protein, and variants thereof, in animal models of muscle injury; identifying genes specifically expressed in satellite stem cells and identifying and validating gene targets of the Wnt7a pathway; establishing and performing cell based screens to identify small molecules that enhance satellite stem cell number; and finally, selecting the best therapeutic option. While reviewers agreed that this proposal could make a significant impact if successful, they felt that much of the work falls outside the scope of the RFA and would be better suited for a Basic Biology grant. Specifically, reviewers described many aspects of the application as early assay development such as identification of a genomic signature of satellite stem cells. They noted that the proteomic screen proposed is a target discovery effort and explicitly out of the scope of this award. Reviewers also questioned the rationale for targeting the Wnt7a pathway systemically, which could affect many other cell types in the body. They would have appreciated data addressing the specificity of the Wnt7a pathway to skeletal muscle satellite stem cells. Reviewers found the feasibility of the proposal to lead to a development candidate difficult to assess. The preliminary data was sparse and inadequately discussed. For example, there is no data demonstrating an effect of Wnt7a on satellite cells following systemic delivery in mice. They also expressed concern whether a development candidate could be achieved in three years given the stage of the research, for example, the inclusion of target discovery and validation, and that cell-based assays to identify compounds that stimulate Wnt7a pathway signaling have not yet been developed. As sufficient numbers of satellite stem cells are unobtainable, the applicant proposes to use alternative cell sources, without addressing how accurately these cells model signaling in bona fide satellite stem cells. Reviewers were also concerned that the library of compounds to be screened is quite small and comprised mostly of drugs, which are likely to be inhibitors rather than activators. They noted that the likelihood of finding hits may be low. Reviewers noted that, even if successful, the end result of this proposal would likely be a lead candidate, requiring extensive additional preclinical work, not a development candidate ready for IND-enabling studies. The reviewers noted that the team brings together a wide variety of backgrounds and experience to the project, and have well demonstrated track records for the approaches. However, it is not clear that any of the team members, outside of one external consultant, have experience with satellite stem cell biology. Overall, while reviewers agreed that muscle wasting diseases represent an important unmet medical need, they found much of the research described in this proposal to be basic, rather than translational, and did not believe that a development candidate would result from it.
- Darin Weber
- Joy Cavagnaro