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Steece-Collier Lab

 

Lab Personnel

Overview

Gene Therapy in PD

There remain several unmet clinical needs in Parkinson’s disease (PD) including waning and incomplete efficacy of symptomatic therapies, unfettered disease progression, and development of medication side-effects (i.e., levodopa-induced dyskinesias (LID)). CaV1.3 calcium channels are therapeutic targets of intense interest in PD. Clinical and preclinical studies have revealed that pharmacological dosing required for meaningful target engagement is currently not achievable without risk of off-target side effects impacting peripheral organs and unintended brain regions. Accordingly, we developed an RNA interference (RNAi)-based vector approach utilizing adeno-associated virus (AAV) expressing a short-hairpin (sh)RNA against CaV1.3 channels to provide potent, target-specific silencing of these channels that become dysfunctional in the parkinsonian striatum.

Our proof-of-concept studies, initially focusing on the antidyskinetic efficacy of this RNAi therapeutic, were first performed in rat models of PD. Based on exceptional promise in these models of young and aged parkinsonian rats, we have now brought this therapy into the nonhuman primate (NHP) model of PD, which has greater predictive value for a complex human disease like PD. These most recent studies provide unprecedented evidence that MRI-guided intraputaminal AAV-CaV1.3-shRNA in aged (25-29yrs) male and female nonhuman primates with long-standing (8mos) moderate-to-severe parkinsonian motor deficits results in a significant progressive reversal of motor deficits in the absence of pharmacotherapy, with some aspects including postural instability and motivation-based fine-motor performance returning to normal/pre-parkinsonian baseline. This contrasts maintenance of stable moderate-to-severe disability in those receiving the control/scrambled vector (AAV-SCR-shRNA). AAV-CaV1.3-shRNA recipients also demonstrate maintained levodopa motor benefit lost in these aged, parkinsonian subjects receiving the AAV-SCR-shRNA vector, similar to end-stage PD. Lastly, AAV-CaV1.3-shRNA recipients showed unprecedented, near-complete prevention of LID induction despite long-term (5.5 mos), twice-daily, dose-escalation levodopa. If the current gene therapy findings can be translated into a clinical application with a similar magnitude, this would provide a much-needed breakthrough in treatment of individuals with PD.  

Over the past 30+ years, I have maintained my dedication to the development of improved therapeutics for individuals with Parkinson’s disease (PD) with particular emphasis in understanding how striatal pathology impacts therapeutic efficacy and/or side-effect development in PD. Over the past 15+ years, our research has resulted in a series of studies examining the structural reorganization of cells and circuits in the basal ganglia associated with graft- and levodopa-induced dyskinesias (LID), and molecular triggers that result in failure of DA treatment strategies. In one of our recently completed grant (R01NS105826), our research delving into the realm of ‘personalized medicine’, examined the impact of a common human single nucleotide polymorphism (SNP) on the on the ability to remodel the parkinsonian striatum with new DA terminals using neural grafting in a CRISPR knock-in rat model of the human SNP rs6265 BDNF as a model system. Our current funding includes one competitively renewed R01 grant from NINDS (R01NS110398), an award from SPARK-NS (https://sparkns.org/programs/projects/) and a private family foundation award to continue the development of our very promising gene therapy that shows strong indication of heading toward clinical development in the next several years.

Specifically, these studies involving multiple relevant models of PD are aiming to define the capacity of novel adeno associated (AAV)-CaV1.3-RNA(i)interference therapeutic agents that provide region specific, gene level silencing of a particular population of calcium channels, CaV1.3 channels, that are therapeutic targets in the PD brain. Our most recent research demonstrates that administration of this spatially controlled RNAi gene therapy demonstrates an unprecedented trifecta of benefits including the ability to provide disease modification (i.e., reversal long-standing parkinsonian motor deficits “OFF” medication), enhancement of motor benefit of levodopa, and amelioration the common LID side-effect that impacts up to 90% of patients. Our continuing investigations are exploring the therapeutic utility of our gene therapy agents in different patient populations by using relevant models of PD, and searching for mechanism underlying these dramatic benefits. These efforts will enhance progress toward early phase clinical testing approval, and allow for development of additional approaches to provide the improved therapeutics for individuals with PD.

Research Groups