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Targeted Therapeutics for Parkinson’s and related disorders: Hopes and Challenges

Wyss EventLecture

Hosted by Wyss Core Faculty David R. Walt, PhD, Diagnostics Grand Rounds brings clinicians with unmet needs to the Wyss Institute. The goal of these sessions is to inform technology developers about important clinical problems that can help them direct their technology development efforts. Presenters are asked to identify diagnostic needs that will have an impact on the quality of care they deliver.

The greatest challenges in effectively slowing the progression of neurodegeneration are their chronicity and heterogeneity. Chronicity brings with it challenges of early diagnosis, biomarkers that meaningfully track progression and extraordinary difficulty in design and execution of clinical trials. Extreme heterogeneity in clinical presentation, rates of progression and presumably genetic and environmental etiology amplifies the usual challenges of precision medicine, namely to target therapeutics appropriately to the right patient at the right time.

One unifying anchor of most common neurodegenerative diseases is the fundamental protein-folding pathology that defines each disease. Dr. Khurana’s group uses this common pathology, albeit also heterogeneous and complex, as an anchor for studies in precision therapeutics for Parkinson’s and related disorders. In the case of these disorders, the centrally perturbed protein is alpha-synuclein, a highly abundant protein in neurons.

They pursue a dual program in Dr. Khurana’s laboratory. First, pursuing a systems cell biology approach to utilize the alpha-synuclein interactome to better understand the myriad genetic and environmental factors that collude to alter disease risk and resilience. A central model that connects their basic biological tools to the patient is the induced pluripotent stem cell system that has the potential to capture the complexity of an individual patient and patient populations “in the dish.” Second, in more nascent work, they strive to develop methodologies that more accurately quantitate the progression phenotypes of patients with a combination of biometrics, soluble and skin-based biomarkers and brain-penetrant radiotracers that bind alpha-synuclein. Establishing a clinical trial incubator in their group in which trials will proceed in parallel in patients and their derivative stem-cell models.

Across the spectrum of work in Dr. Khurana’s lab, they have seen tremendous progress but there are many challenges and unmet needs. A central aim of this talk will be to outline these with the hope of finding cross-cutting and collaborative solutions.

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