Steece-Collier Lab
Lab Personnel
- Kathy Steece-Collier, PhD, Primary Investigator
- Jennifer Stancati
- Carlye Szarowicz
- Asha Savani
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.
Precision Medicine
While there are a number of therapeutic options for individuals with Parkinson’s disease (PD) these therapies do not work uniformly well in all patients. Indeed, a recent retrospective analysis of the ‘ELLDOPA’ study reported that early-stage PD subjects receiving equivalent doses of the antiparkinsonian medication levodopa experienced a magnitude of response ranging from a 100% improvement to a 242% worsening in their parkinsonian motor disability. This example underscores the incredible heterogeneity in clinical response to standard-of-care anti-parkinsonian therapy, even when disease severity is taken into account. Similar findings have been reported over the past several decades for the experimental ‘regenerative medicine’ approach of nerve cell transplantation aimed at replacing cells that die in PD. While some PD patients have shown marked and lasting benefit following engraftment of new dopamine (DA) neurons, many have also shown no or limited benefit; and a significant subpopulation has developed devastating transplant-related side-effects. As clinical transplantation trials are currently reemerging worldwide it remains uncertain what specific risk factors negatively impact clinical responsiveness to this approach, which offers hope for a much needed additional therapeutic option for the approximately 4 million individuals suffering with PD. One approach to deconstructing the complex range of responses to therapy is identification of common genetic variants that may influence therapeutic efficacy.
We have identified one candidate genetic variant, with prevalence of up to 40% in the human population that may be useful in this regard. Specifically, a functional single nucleotide polymorphism (SNP) ‘rs6265’ in the Bdnf gene for brain-derived neurotrophic factor (BDNF) that results in dysfunctional BDNF release from neurons. BDNF is critical for structural integrity of, and normal communication between neurons in brain regions associated with DA neuron transplantation therapy. Our lab has been using a CRISPR knock-in rat model of the human rs6265 BDNF variant to test the hypothesis that this SNP is a genetic “risk factor” that underlies the reduced or aberrant clinical response of some PD individuals to the brain repair strategy involving transplanting new DA producing brains cells.
The overall goal for PD (or any disease) is to tailor treatment to the individual characteristics of each patient to provide safe, effective, and precise interventions with minimal complications. Findings from the current research for this project will guide ongoing and future clinical grafting trials by providing scientific insight into whether this particular SNP (rs6265), which occurs in up to 40% of the general population will impact, either negatively or positively, an individual’s response to the regenerative medicine approach of DA neuron transplantation.