Early Translational III
Anorexia nervosa (AN) is a complex developmental illness that affects 0.3-0.7% of women across the nation. Although anorexia has the highest mortality of any psychiatric illnesses, we do not have FDA approved treatments. Symptoms of anorexia include extreme food-induced anxiety and reduced intake of food resulting in weight loss to the point of emaciation or death. Patients with anorexia face debilitating medical consequences during their illness, many of which can become long-lasting, such as failure to produce blood cells, failure of the kidneys, osteoporosis and reproductive failure. Alleviating symptoms has the remarkable potential to reduce mortality and morbidity. Genetic studies show that up to 80% of the risk of becoming ill with anorexia is heritable. Our recent data identify specific changes in the DNA sequence that contribute to the risk of becoming ill and provide much needed guidance on which molecular pathways to target with new treatments. However, the lack of human cellular models has blocked any progress thus far. Potential alternatives such as mouse models do not have the symptoms associated with this human illness. Generating human neurons from skin fibroblasts through stem cell technology offers a great opportunity to develop a drug screening platform to rapidly test thousands of drugs. This proposal establishes such a screening system where we will test promising leads from the clinic that target human genetic pathways implicated in anorexia.
Statement of Benefit to California:
Anorexia nervosa has the highest mortality of any psychiatric illness and results in significant death and disability within California. Anorexia nervosa is poorly understood and effective treatments are lacking with devastating consequences for patients and their families. Our innovative approach that combines stem cell technology and genetics to accelerate drug discovery offers a remarkable opportunity to make advances in treatment that was not previously possible. Our approach will not only relieve the enormous burden on patients and families but also on the healthcare resources across California. Stimulating drug discovery technologies will also create jobs through new biotech and engineering ventures that are essential to keep California's economy strong.
The objective of this Development Candidate Feasibility (DCF) application is to develop a "disease-in-a-dish" model of the eating disorder Anorexia Nervosa (AN), which will then be used to test candidate drugs for the ability to reverse the AN phenotype. The principal investigator’s (PI’s) hypothesis is that iPSC cellular models developed from AN subjects will show genetically determined alterations that lead to reduced synaptic release of a key neurotransmitter. The investigators have identified variants of three genes that contribute to the risk of AN. The applicants propose to generate iPS cells from skin fibroblasts of AN subjects and use these cells to derive neurons. These cells will be used to define a phenotype that will be used to develop a quantifiable assay. Such an assay will be used test various compounds active on neurons to reverse AN-associated neuronal phenotypes. The investigators anticipate that successful achievement of their Aims will enable future development of one of the candidate drugs, or a chemical derivative thereof, for therapy of AN. Objective and Milestones - Repurposing drugs already approved for other neurological indications is noted as an expeditious strategy to screen potential therapeutic candidates for new indications. - The applicant has identified the key milestones to achieve initial proof of concept. Rationale and Significance - The scientific rationale for the fundamental role of neurotransmitter signaling in AN raises an intriguing hypothesis but is not based on compelling evidence. - The approach of using iPS cell-derived neurons is attractive; however, the rationale is weak that genetically determined alterations that lead to putative dysfunction of a key neurotransmitter provides a mechanistic basic for a complex disease. - Since there is no FDA approved medication for AN, such a medication would have an immediate impact for the 0.5% of women with this illness. Research Project Feasibility and Design - The outlines of the research plan are reasonably straightforward; however it is not well developed and there are a number of places in which experimental evidence is lacking. - The investigators do not provide enough information on allele frequencies to assess whether they are likely to obtain the desired sets of iPS cell lines and controls with representative genotypes. -The applicants should first spend time to identify patients with a mutation (or mutations) of interest, and then generate the iPSC. - The investigators do not provide sufficient information to assess the feasibility of their key assays - neurotransmitter release and frequency of specific neuron firing. - They give almost no information on how they propose to carry out mechanistic studies to explain phenotypes observed. - The assessment of two models of firing of specific neurons is not discussed. Qualification of the PI (Co-PI, and Partner PI) and Research Team - The PI and Co-PI have the necessary expertise to conduct the experiments, based on the preliminary data included in the application. - It is not clear that PI has the necessary skills and experience to direct this ambitious translational project. Collaborations, Assets, Resources and Environment - The collaboration with one of the co-investigators who has developed a similar program in another condition is essential; the importance of another co-investigator is less clear. - The collaborative relationships are in place and the PI and co-PI have everything they need at their disposal to conduct the described experiments. - No letter of support was provided by the chemical biology and drug discovery resource. Responsiveness to the RFA - The proposal is responsive to the RFA