Steece-Collier Lab

 

Lab Personnel

Overview

Gene Therapy in PD

One often debilitating side-effect of standard pharmacotherapy for Parkinson’s disease (PD), levodopa administration, are unwanted involuntary movements known as levodopa-induced dyskinesia (LID). There is currently one FDA approved drug that partially reduces LID in a subpopulation of patients for a limited amount of time, yet up to 90% of individuals with PD develop this side-effect. The L-type calcium channel CaV1.3 found in a brain region called the striatum is a target of interest for LID prevention. In PD, a loss of nigral dopamine (DA) neurons that project to the striatum results in dysregulation and overactivity of striatal CaV1.3 channels leading to synaptic pathology that appears to be involved in LID. While initial studies in animal models of PD using pharmacological CaV1.3 channel antagonists showed a dose-dependent reduction of LID, the effects were partial and transient which we hypothesized was related to the fact that currently available CaV1.3 antagonist drugs incompletely inhibit these channels. To provide unequivocal target validation, free of pharmacological limitations, we developed a rAAV-CaV1.3-shRNA to provide continuous, high potency, target-selective, mRNA-level silencing of striatal CaV1.3 channels.

We have shown that gene level silencing of striatal CaV1.3 channels in young adult male parkinsonian rats, prior to the introduction of levodopa provides complete and sustained protection against the induction of LID even with high doses of daily levodopa. We also observed that rAAV-mediated CaV1.3 silencing in young adult male parkinsonian rats with already established LID could substantially reverse these behaviors. Because PD is a disease generally occurring in aged individuals (~60 years old), we are currently extending these translational studies to determine whether this marked anti-dyskinetic effect is maintained in aged parkinsonian male and female rats. Initial indications are that sex does impact the viability of this therapy, which is a topic of continuing investigation in the lab.

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 and would allow the most powerful antiparkinsonian therapy ever identified (i.e.: levodopa) to work unabated through the duration of the disease.  

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.

Research Groups