Early Translational III
The lack of any biological or genetic predictors of clinical utility of specific medication for Major Depressive Disorder (MDD) results in random first choice and costly systematic follow-up assessment. Given the lifetime prevalence in the US estimated at 17% this empirical approach translates into millions of people going through months of ineffective medication increasing the morbidity and the cost of treatment (in 2000 the burden of depression in US was ~$83 billion). Here we propose a reliable in vitro test to predict the best existing drug for the new patients with MDD. Recent genetic studies suggested that genetic determinants are responsible for variable response to antidepressant. Therefore we put forward an in vitro assay based on the patient-derived neurons to measure and classify the variable response to antidepressant. We combined a state of the art techniques and entirely novel computational algorithms to build a reliable in vitro diagnostic platform to predict the best 1st choice antidepressant for each patient with MDD. In the future, this approach could be adapted to other psychiatric disorders.
Statement of Benefit to California:
The lack of any biological or genetic predictors of clinical utility of specific medication for Major Depressive Disorder (MDD) results in random first choice and costly systematic follow-up assessment. Here we propose a reliable in vitro test/diagnosis methodology to predict the best existing drug for the new patients with MDD. An effective, straightforward, and understandable way to describe the benefits to the citizens of the State of California that will flow from the stem cell research we propose to conduct is to couch it in the familiar business concept of “Return on Investment”. The novel therapies and reconstructions that will be developed and accomplished as a result of our research program and the many related programs that will follow will provide direct benefits to the health of California citizens. In addition, this program and its many complementary programs will generate potentially very large, tangible monetary benefits to the citizens of California. These financial benefits will derive directly from two sources. The first source will be the sale and licensing of the intellectual property rights that will accrue to the state and its citizens from this and the many other stem cell research programs that will be financed by the CIRM. The second source will be the many different kinds of tax revenues that will be generated from the increased bio-science and bio-manufacturing businesses that will be attracted to California by the success of the CIRM.
The goal of this Development Candidate Feasibility proposal is to develop a diagnostic test that will predict clinical responsiveness to serotonin reuptake inhibitors (SSRI) for major depressive disorder (MDD). The applicant proposes to derive neurons from MDD patients with documented responses to several commonly prescribed antidepressants and develop in vitro assays to characterize their synaptic activity and calcium signaling properties. The applicant will evaluate the effects of these drugs in order to develop reference signatures that are predictive of clinical response. Three aims have been proffered to achieve these goals including 1) optimization of protocols to derive and characterize 5-HT (serotonergic) neurons from human induced pluripotent stem cells (iPSC); 2) assessment of the effects of SSRIs on MDD patient-derived neurons; 3) optimization of machine learning and statistical algorithms for correlating in vitro phenotypes with patient response. Objective and Milestones - While there is a clear need for better antidepressant selection, it is not apparent that selecting one SSRI over another will overcome this problem. - The clinical viability of this approach is questionable. Clinicians and patients are unlikely to wait several weeks before initiating treatment unless major effects could be anticipated. - Project milestones are well designed and described. Rationale and Significance - The underlying premise of this application is precarious, hinging on an assumption that genetic variability in neurons alone could sufficiently account for differences in patients’ responses to SSRIs. This unlikely scenario precludes a potentially significant contribution of genetic variation on metabolism as well as roles for other cell types including astrocytes, which are known modulators of synaptic activity. - It is not clear that the use of induced neuronal cultures for stratification of patient response to SSRIs would prove superior to other methodologies for measuring genetic variability. - The application of optogenetics, while cutting-edge, is not well justified for use as an in vitro diagnostic compared to simpler methodologies. - The proposal attempts to develop a personalized medicine approach for an important unmet medical need, and if successful, could lead to major economic and medical benefits. Research Project Feasibility and Design - There are no convincing preliminary data to suggest that therapeutically meaningful differences in drug response would be detected through the proposed outcome measures. - No compelling data are provided to suggest that proposed assays would be sufficiently sensitive and specific to differentiate true responses from false or irrelevant ones. The surrogate drug experiments were not convincing in this regard due to the amplitude of their effects. - The technical ability of the applicant to reproducibly generate human neurons from induced pluripotent stem cells and conduct assays with them is indisputable. - Feasibility would have been strengthened if data from 5-HT neurons following SSRI treatment had been included. - The use of patient specimens with defined SSRI clinical responses is a strength. - It is not clear from the research plan whether certain complementary controls would necessarily be included, such as individuals with known defects in SSRI response pathways, or patients who respond to one SSRI class but none of the others. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI has a strong record of training and achievement in neural stem cell biology and possesses the requisite expertise to conduct the proposed experiments. The co-investigators provide valuable experience in procuring MDD patient samples and stratifying them by SSRI response. An expert in data analysis is an additional strength. - While the research team has an impressive breadth of expertise, additional clinical psychiatric input might have been helpful for addressing substantial clinical gaps in the proposal. Collaborations, Assets, Resources and Environment - Collaborations are key to the success of this project. While letters of support are encouraging, there is no discussion of a specific communication plan. - The resources and environment for the neural studies are outstanding. Reviewers were uncertain whether the collaborator in private practice would have the appropriate environment for generating patient biopsies that are suitable for iPSC derivation. There is no plan described as to how samples would be stored, handled and transported. Responsiveness to the RFA No relevant concerns were highlighted by reviewers under this review criterion.