What Are the Gene Therapy and Growth Factor Approaches for Parkinson’s Disease?
Current Parkinson's disease (PD) treatments leave patients with inadequate control of symptoms as the disease progresses, creating a significant unmet need for PD treatments that stably restore dopaminergic network function over the long term. By meeting this need, and providing therapies that slow disease progression and deliver robust and long-lasting functional benefits, we can meaningfully improve patients' quality of life.
Growth factors hold considerable promise for disease modification in neurodegenerative disorders such as PD, as they can potentially protect and restore degenerating neurons while also enhancing their functional activity. Based on promising results in neurotoxin lesioned animal models, the following four growth factors have progressed to clinical trials in PD patients:
· platelet-derived growth factor (PDGF)
· glial cell line derived neurotrophic factor (GDNF)
· neurturin (NRTN)
· cerebral dopamine neurotrophic factor (CDNF)
Although multiple clinical trials with growth factors have now been performed in PD, the results have been mixed and inconclusive, outlining the importance of thoughtful study design with regard to dosing, therapeutic delivery paradigms, brain region coverage, and the development of PD patient stratification criteria. However, as part of these clinical studies, the glial cell line-derived neurotrophic family of GDNF and NRTN ligands have shown evidence that they can induce dopaminergic dendritic sprouting or improve F-DOPA uptake. This supports the hypothesis for GDNF and NRTN in PD but further emphasizes the need for thoughtful delivery and robust neuronal regional coverage.
Gene therapy is an attractive approach with direct brain delivery to impart a durable effect on neuronal function through the introduction of growth factor genetic material to functionally recover dopaminergic signaling by improving neuronal health. Ongoing clinical gene therapy trials in PD are either focused on enzymatic enhancement of dopamine production or the neurotrophic restoration of the nigrostriatal pathway to improve dopaminergic network function. Here we will focus on the ongoing neurotrophic research in PD gene therapy.
Preservation and regeneration of the nigrostriatal pathway is a critical hypothesis related to extending PD patient quality of life and functioning, as well as reversing symptoms. In addition to dopaminergic neuronal loss, the brains of patients with PD also exhibit a loss of endogenous neuronal growth factors in affected brain regions. However, although neurotrophin therapy may seem like the ideal approach for neurodegenerative disease, the use of growth factors as drugs presents major challenges because of their protein structure, which creates serious hurdles related to accessing the brain. The inability to consistently deliver growth factors to the disease-relevant brain areas has resulted in the mixed and inconclusive clinical data generated to date. To address these challenges, direct infusion of in vivo growth factor gene therapies into target brain regions has progressed to clinical trials in patients with PD.
Two growth factors, GDNF and NRTN, have garnered significant attention in the novel in vivo gene therapy field. AAV2 NRTN (CERE-120) has been evaluated in multiple Phase 1 and Phase 2 studies examining bilateral putaminal infusions and bilateral putaminal-plus-nigral infusions. Despite successful Phase 1 trials, patients in the follow-up Phase 2 trials presented with mixed results and failed to meet their respective primary endpoints. Continued issues with neuronal coverage and delivery of the drug contributed to the lack of efficacy. As a consequence, there are no trials currently active for NRTN gene therapy.
Accurate and reproducible delivery is a critical aspect of gene therapy, particularly for neurologic disorders, as has been evidenced by prior clinical experience with intraparenchymal delivery. Suboptimal coverage of the putamen, resulting from delivering conservative volumes, has been identified as one of the most common reasons underlying the lack of success in the earliest gene therapy clinical trials. It has now been rationalized that improving delivery with MRI-monitored convection enhanced delivery (CED) might overcome the limitation of insufficient putaminal and nigral neuronal coverage to achieve clinical improvements in motor function.
Only AAV2 GDNF is active in two clinical gene therapy trials for PD. AAV2 GDNF has been used in one Phase 1 dose-escalation study that closed in 2022. This study demonstrated that AAV2 GDNF was well tolerated in participants with advanced PD up to 5 years following treatment. Moreover, a Phase 1b study utilizing MRI-guided bilateral putaminal CED delivery of the study drug has just completed enrollment (NCT04167540).
AAV2 GDNF administration in the ongoing Phase 1b study has so far demonstrated an encouraging safety profile with a preliminary efficacy signal. The neurosurgical procedure was well tolerated, and all 11 participants have completed 9 or more months of clinical follow-up. Importantly, putaminal coverage was >60%. No serious adverse events were associated with AAV2 GDNF. Reported adverse events primarily occurred peri-operatively or were related to underlying PD.
Most participants in the Mild PD Cohort have demonstrated an overall stable clinical picture with little change on Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), PD motor diary, or levodopa equivalent daily dose (LEDD) measures. Participants in the Moderate PD Cohort demonstrated improvement or stability on several motor scales and PD motor diary, in the presence of reduced LEDD.
Although the placebo effect limits interpretation of small open-label studies such as this, these preliminary findings show stabilization in mild PD and possible early improvements in the moderate PD participants. Further longitudinal evaluation and a controlled study is planned to confirm these initial findings.
Neurotrophic growth factor gene therapy remains a promising and potentially disease-modifying therapeutic approach to long-lasting improvements in PD patient quality of life and functioning. During his upcoming talk at the 6th World Parkinson Congress in Barcelona, Dr. Bankiewicz will review data from current growth factor gene therapy trials for PD, highlighting recent advances in study design and surgical approaches to effectively test the growth factor hypothesis in PD.
Krystof S. Bankiewicz, MD, PhD, serves as a tenured professor at The Ohio State University and holds the Gilbert and Kathryn Mitchell Endowed Chair at The Ohio State University Wexner Medical Center. He also serves as director of The Ohio State University’s Brain Health Performance Center. He is also a presenter on this subject at WPC 2023. View the Scientific Program here.
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions or positions of the World Parkinson Coalition®