Early Translational II
Parkinson’s Disease (PD) is the most common neurodegenerative movement disorder. It is characterized by motor impairment such as slowness of movements, shaking and gait disturbances. Age is the most consistent risk factor for PD, and as we have an aging population, it is of upmost importance that we find therapies to limit the social, economic and emotional burden of this disease. Most of the studies to find better drugs for PD have been done in rodents. However, many of these drugs failed when tested in PD patients. One problem is that we can only investigate the diseased neurons of the brain after the PD patients have died. We propose to use skin cells from PD patients and reprogram these into neurons and other surrounding cells in the brain called glia. This is a model to study the disease while the patient is still alive. We will investigate how the glial surrounding cells affect the survival of neurons. We will also test drugs that are protective for glial cells and neurons. Overall, this approach is advantageous because it allows for the study of pathological development of PD in a human system. The goal of this project is to identify key molecular events involved at early stages in PD and exploit these as potential points of therapeutic intervention.
Statement of Benefit to California:
The goal of this proposal is to create human cell-based models for neurodegenerative disease using transgenic human embryonic stem cells and induced pluripotent stem cells reprogrammed from skin samples of highly clinically characterized Parkinson’s Disease (PD) patients and age-matched controls. Given that age is the most consistent risk factor for PD, and we have an aging population, it is of utmost importance that we unravel the cellular, molecular, and genetic causes of the highly specific cell death characteristic of PD. New drugs can be developed out of these studies that will also benefit the citizens of the State of California. In addition, if our strategy can go into preclinical development, this approach would most likely be performed in a pharmaceutical company based in California.
The overall goal of this Development Candidate (DC) Award application is to understand and modify neuroinflammation as a means for treating Parkinson's disease (PD). The principal investigator╒s (PI) group has recently shown that a specific nuclear receptor plays an essential role in the transcriptional repression of pro-inflammatory neurotoxic factors. By targeting the receptor or other relevant nuclear receptors, the applicant proposes to modulate the effects of neuroinflammation to ameliorate impairments associated with PD. The applicant proposes a general strategy to identify small molecule agonists of the nuclear receptor using PD patient-derived induced pluripotent stem cells (iPSC) and their derivatives. In the first year, fibroblasts from PD patients with well-studied clinical parameters will be obtained from the partner PI, reprogrammed to iPSCs and subsequently differentiated into dopaminergic (DA) neurons, astrocytes and microglia. These procedures will serve as the basis for modeling PD-associated defects and exploring the role of the nuclear receptor and other molecules in the disease process. In the second year, the applicants will continue to develop assays while exploring hypotheses relating to the role of inflammation and the mechanism of nuclear receptor function in PD-derived neural cells. In the final year, the applicant proposes to identify molecular signatures of neuroinflammation in PD that may serve as targets for therapeutic intervention. In addition, specific compounds will be defined as potential anti-inflammatory treatments for PD patients. If clinically used molecules are identified, the applicant proposes to correlate experimental results with patient data and potentially prepare for a clinical trial. Reviewers believed that the proposed research, which is largely focused on target discovery and mechanistic investigation, was not sufficiently mature to meet the objectives of the RFA. While they acknowledged that the nuclear receptor is a compelling target, reviewers were not convinced of the underlying assumption that reduction of inflammation in patients with PD would necessarily be of clinical benefit, noting abundant evidence that inflammation can in fact be regenerative in the brain and elsewhere. It was also unclear whether there would be sufficient candidates regulating receptor expression that could be brought to the clinic other than commonly available non-steroidal anti-inflammatory drugs such as ibuprofen. Reviewers worried that the lack of a defined pharmaceutical plan to co-develop such drugs could limit the number of candidates that could be effectively translated for clinical consideration. Although identification of a new, clinically safe drug could in theory have high impact, reviewers felt the most likely benefits to emerge from this work would relate to development of microglial differentiation techniques as well as hiPSCs-based tools for future drug discovery efforts. Reviewers raised serious concerns about the feasibility of the overall project. Although the aims are broad and comprehensive, many are contingent on techniques that have not been developed, or on premises that are not firmly established. For example, the assays proposed in Aim 3 to evaluate integration and uptake of synuclein in PD-derived neural precursors vs. controls might not prove meaningful, as the significance of synuclein uptake has not been convincingly demonstrated. Other aims rely heavily on the protocols that have yet to be defined, such as the differentiation of hiPSCs to microglia. While the PI acknowledged that this goal would be challenging, some reviewers considered the need for this data a prerequisite for consideration under this RFA. Others worried that iPSC-derived astrocytes might not accurately reflect the heterogeneity found in the central nervous system, a point that was not addressed in the application. Given these uncertainties, reviewers questioned whether the proposed co-culture system would recapitulate the necessary physiological interactions for modeling PD processes, and whether it would ultimately be possible to assess the biological effects of nuclear receptor agonists in vivo by using human PD iPSC derivatives. In addition to these specific criticisms, reviewers found the overall research plan to be diffuse and lacking the pragmatic focus necessary to produce a single well defined development candidate. Although some compelling ideas were presented, the overall experimental design and milestones were more suited to a discovery-based research project, with each specific aim potentially the subject of an independent investigation. Reviewers praised the PI as a leading, internationally recognized authority in the field of neuroscience with outstanding creativity, expertise and productivity. The Co-PI was considered highly qualified, particularly in the areas of transcriptional regulation and inflammation. The contribution of the partner PI╒s expertise and unique access to PD patients and analysis was viewed as an exceptional asset, and the reviewers found the collaborative efforts of the 3 leaders (PI, Co-PI and Partner PI) to be well synergized. The institutional support and resources were judged to be excellent. Overall, reviewers agreed that proposed research is not sufficiently mature to produce a candidate suitable for IND preclinical development in three years. Despite compelling hypotheses and an exemplary team of investigators, reviewers found the underlying rationale and feasibility to be inadequately supported and therefore did not recommend this application for funding. PROGRAMMATIC REVIEW A motion was made to move this application into Tier 1, Recommended for Funding, with a suggestion to reclassify the project as a Development Candidate Feasibility (DCF) Award with concomitant reduction of budget and scope. Most reviewers maintained that the overall project was scientifically immature, and no individual portion could adequately meet the objectives of the Early Translational II RFA even as a DCF Award. Although there is value in encouraging a PI of this stature to work in PD, reviewers felt strongly this reason alone was insufficient and inappropriate to merit a recommendation for funding when balanced against a poorly responsive and scientifically flawed proposal. Reviewers also highlighted that fact that a different and more mature proposal addressing PD was already in Tier 1. The motion was withdrawn. Due to the confidence afforded to the PI and the interesting, albeit premature ideas presented, reviewers suggested that a Basic Biology RFA might be a more appropriate call for this proposal.