Early Translational II
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death in the U.S. This devastating disease affects 1 child in every 6,000-10,000 live births, with a North American prevalence of approximately 14,000 individuals. The disease is characterized by the death of spinal cord cells called motor neurons that connect the brain to muscle. Death of these cells causes muscle weakness and atrophy, which progresses to paralysis, respiratory failure and frequently death. The three different types of SMA differ in severity and prognosis, with Type I being the most severe. SMA is caused by a genetic defect that leads to reduced levels of a single protein called SMN. There are currently no approved therapies for the disease. The existing treatments for SMA consist of supportive care for the respiratory and nutritional deficits, for example ventilation and feeding tubes. Previous attempts to develop drugs using conventional technologies, such as cultured cancer cells or cells derived from animals have been unsuccessful. These failures are likely due the fact that previous attempts used cell types that don’t reflect the disease or aren’t affected by low levels of the SMN protein. Our approach uses patient-derived motor neurons, the specific cell type that dies. We will conduct drug discovery experiments using these motor neurons to find potential therapeutics that increase the levels of the SMN protein in these diseased cells. Induced pluripotent stem cell (iPSC) technology allows us to take skin cells from patients with SMA, grow them in a dish, and turn them into motor neurons. We are conducting high-throughput screens of potential drugs with these cells to identify drug candidates that increase SMN protein levels in motor neurons derived from SMA patients. An added advantage to our approach is that we can test our drug candidates in motor neurons from many different patients, with different disease subtypes and from different ethnic backgrounds. We have generated iPSCs from many patients with SMA and we will test compounds for effectiveness against this cohort. These studies will give us an indication of the effectiveness of our compounds across patients before moving into costly and lengthy clinical trials. If our drug candidate is successful, it could be the first effective therapeutic available for SMA. It will increase the amount of SMN protein and prevent motor neuron death. Halting the death of spinal cord motor neurons prevents the progressive weakness and muscle atrophy. We anticipate that this would prevent disability in Type III patients. For Type I and II patients, we believe such a therapy would mitigate respiratory and feeding challenges and allow lifespan increase. The sponsoring institution has integrated iPSC-based drug discovery capabilities, ranging from stem cell line production, high throughput drug screening and medicinal chemistry. Accordingly, this institution is uniquely positioned to achieve the aims of this grant.
Statement of Benefit to California:
Spinal muscular atrophy (SMA) is the second-most common autosomal-recessive disorder and leading genetic cause of death of infants in the U.S. We estimate that there are up to 1,500 SMA patients currently living in California, with 100 new cases diagnosed in California every year. The CIRM Early Translational II Awards is intended to fund studies that will propel drug discovery forward for many devastating diseases. In keeping with this mission, we propose to leverage iPSC technology to generate disease-relevant cell types from patients themselves for a high throughput drug screen. A successful therapy for SMA would lead to significant cost savings to California’s health care system, and would provide relief to families of patients with this devastating disorder. Given that there are not many successful drugs in the making for neurological diseases such as ALS, SMA, Parkinson’s disease or Alzheimer’s disease, our project should significantly impact drug discovery in this area by introducing iPSC technologies as a valid drug discovery and development platform. The application of iPSC-based disease modeling and drug discovery to SMA is highly innovative and represents the opportunity to establish worldwide leadership for California in this emerging field. Furthermore, the sponsoring institution will fund over 70% of the direct costs during the timeframe of this award. Accordingly, the 3:1 leverage provides great opportunity to magnify the effect of a CIRM award. Our research program will also create new, high-paying jobs in California, and will stimulate California’s economy by creating new research and clinical tools. These activities will continue to strengthen California’s leadership position at the forefront of the stem cell and regenerative medical revolution of the 21st century.
This is a development candidate (DC) award application that proposes to identify small molecules that increase the expression of survival motor neuron protein 1 (SMN1) in spinal muscular atrophy (SMA) patient-derived motor neurons. In most SMA patients, mutations in the SMN1 gene result in low levels of expression of functional SMN1 protein in motor neurons. The resulting motor neuron degeneration leads to muscle atrophy with eventual respiratory failure and death. Drugs that increase SMN1 levels in fibroblasts have proven clinically ineffective and there are no current therapies available for SMA patients. The applicant has successfully derived motor neurons from SMA patient fibroblasts using induced pluripotent stem cell technology (iPSC) and has initiated screening of a large chemical library to identify hits. Hits have been identified that upregulate SMN1 protein in the SMA motor neurons. The proposed research expands upon this initial screen to identify lead compounds for the treatment of SMA. In Aim 1, the applicant proposes to confirm and prioritize hits from the primary screening campaign and identify compounds for lead development. In Aim 2, the applicant will optimize, create in vitro toxicity profiles, and confirm the activity of lead compounds across SMA disease subtypes and genetic backgrounds. In Aim 3, the applicant will test the disease–modifying activity of lead compounds in in vivo models and in vitro against iPSC patient-derived motor neurons and will select a lead clinical candidate ready for IND-enabling studies. Reviewers praised the rationale and the potential impact of this application. The use of patient-derived motor neurons for the identification of a small molecule therapeutic is well justified given the clinical failure of compounds identified using non-motor neuron based screening. These results will have more physiological relevance than screens employing human fibroblasts or cancer lines. Additionally, reviewers uniformly agreed this application is of high potential impact as there are no known therapies for SMA. Further, though SMA has a relatively high incidence rate for an orphan disease, disease incidence is still low enough that it is difficult to attract commercial interest in funding such research and CIRM is a unique source of funding for this project. Reviewers considered SMA an excellent target for iPSC-based drug screening and noted that stem cells are necessary to obtain the physiologically relevant motor neuron. Reviewers expressed enthusiasm for the research plan and overall feasibility of identifying a lead compound ready for IND enabling studies in the proposed timeline. The reviewers were appreciative of the thorough preliminary data and well thought out research plan. The applicant has the necessary high throughput assays in place and the first round of hits have already been identified. Reviewers commended the applicant for using past data and information to inform the experimental plans, specific milestones, and selection processes. The experimental plan to identify a lead candidate is logical and includes the exclusion of non-specific effects and the determination of mechanism. One reviewer remarked that the inclusion of a collaborator with access to large patient populations to obtain cells for screening is a strength of the proposal. Reviewers expressed some minor concerns with the preliminary data and research plan. Reviewers commented that the applicant has not published on the generation of iPSC-derived motor neurons, and the application included only low power micrographs that did not allow determination of morphology. While reviewers believed the applicant’s claim that motor neurons could be produced, they would have appreciated the inclusion of more substantial and supportive preliminary data. Reviewers also noted that the criteria to determine hits from the high throughput screen were not described in sufficient detail. One reviewer expressed a slight reservation that validation data for the secondary screens was not included in the application and indicated that the proposed application is on the borderline of target discovery, an activity excluded in this RFA. However, this reviewer was reassured that the applicant has already identified compound hits and thought it likely that the applicant could identify a lead compound in the proposed timeline. Despite these slight concerns, the reviewers maintained their enthusiasm. Reviewers unanimously agreed the principal investigator (PI) and his/her team are highly qualified to successfully undertake this study. The PI and his/her team have an impressive track record in drug discovery and iPSC research. The relevant expertise, personnel, and equipment required to complete screens and optimize a lead compound are already in place. The budget and commitment to the project is appropriate, and reviewers were highly enthusiastic about the existing clinical collaborations. The environment and institutional commitment to the proposed research were considered impressive. Overall, although minor reservations existed, reviewers were enthusiastic about the excellent PI and team, high impact, and robust research plan. Reviewers agreed that the applicant is likely to identify a lead compound ready for IND-enabling preclinical research by the end of the funding period, thus, the application was recommended for funding.