Early Translational IV
$1 824 720
Anorexia nervosa (AN) is a complex developmental illness that affects 0.3-0.7% of women across the nation, requiring prolonged hospital stays followed by relapse. Although anorexia has the highest mortality of any psychiatric illnesses, we do not have FDA approved treatments. Death in anorexia often arises from suicide following escalating psychiatric symptoms, such as intractable anxiety. The survivors face debilitating medical consequences, many of which can become long-lasting, such as failure to produce blood cells, failure of the kidneys, osteoporosis and reproductive failure. Reducing symptoms has the remarkable potential to reduce mortality, morbidity and a high socio-economic burden. 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 use insights from the clinic to 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. The illness also poses a disproportionately high healthcare burden due to the need for repeated hospitalizationsa that are followed by relapses on discharge. There is a high strain on healthcare resources outside the hospital as the illness becomes chronic due to ineffective treatments. 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 stimulate California's economy.
Anorexia nervosa (AN) is a mental disorder that mainly affects women. It is characterized by self-imposed extreme restrictions in food intake, resulting in malnutrition and sometimes death. Based on evidence that this disorder is highly heritable, the applicant proposes in this Development Candidate Feasibility (DCF) Award application to develop an induced pluripotent stem cell (iPSC)-based model of the disease. Once iPSC have been derived from patients with AN, the applicant intends to differentiate them into neurons thought to be affected in this disorder, to identify a phenotype in those neurons that recapitulates an observed cellular defect in patients, and to screen a library of clinically approved drugs for compounds that reverse the phenotype. It is theorized that such compounds will reduce food-related anxiety, a major symptom in AN, and could be repurposed to treat patients suffering from AN. Objective and Milestones - The proposed research is at a very early stage of the translational pipeline. The applicant has not yet identified a phenotype in the proposed iPSC-based disease model. The objective of this proposal to perform a drug screen for a reversal of a phenotype may therefore not be possible. Rationale and Significance - The application is based on a feasible hypothesis regarding a neuronal dysfunction in AN, and the proposal is well placed to test that hypothesis. However, if the hypothesis is untrue, then the proposed assay cannot serve as an appropriate screening platform. - AN is a major mental disease. The development of an effective medication would be a substantial advance, especially given the limited efficacy of current behavioral treatments and the mortality. - Good preliminary evidence for a strong genetic component to the disease is presented. This supports the idea to use an iPSC-based approach as proposed. Feasibility and Design - Excellent preliminary data from a collaborator’s lab support the ability of the applicant team to model another mental disorder and to generate the desired neuronal cell type from iPSC, but additional data, on AN patient iPSC, would be necessary to convince reviewers that AN can be modeled as proposed. - The proposed assays are suitable for high throughput screening, but if the applicant fails to identify a phenotype in the dish, there can be no screen. It is thus unclear whether the drug-screening portion of the research plan will be executable. - The proposed research plan is feasible in terms of generating and analyzing iPSC-derived neurons. The work may thus progress to a screen, if a phenotype can be identified. Reviewers questioned whether preclinical proof of concept, as required by the RFA for a DCF Award, could be achieved. Qualifications of the PI (Co-PI, Partner PI, if applicable) and Research Team - The principal investigator (PI) has excellent training as a psychiatrist and as a neuroscientist, but his/her publication record is not strong. - The team as a whole has the appropriate expertise to conduct the proposed experiments. Two collaborators, one with stem cell expertise and one with expertise in high throughput screening, are well qualified to fulfill their roles in the project and have excellent records of productivity. The PI can recruit the AN patients with the appropriate genotypes. Collaborations, Assets, Resources and Environment - The proposed collaborations are essential for success. - The institutional support for the PI is good, as evidenced by an appropriate letter of support. - The resources and environment are completely adequate to support the project. Responsiveness to the RFA - Reviewers differed in their opinion whether this proposal is responsive to the RFA. The proposed use of iPSC is essential to the research, thus meeting one of the responsiveness criteria, but some reviewers judged the work to be focused on drug target discovery, and hence outside the scope of these awards. - The proposed disease target is novel to CIRM; it is not represented in CIRM’s translational portfolio.