AAV has become a rising star in innovative drug R&D to treat CNS diseases. In Nov. 02, Cell published an article written by Chinese Academy of Sciences called Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model, marking a significant progress in this innovative modality.
Before the gene therapy shines light on the disease. Parkinson's is traditionally treated by the dopamine precursor levodopa (L-Dopa) or dopamine receptor agonists to restore the activity of basal ganglia (BG) movement control pathways. While L-Dopa is effective, long-term use can be associated with motor fluctuations and dyskinesias (involuntary movements). These side effects may require adjustments to the medication regimen.
In the article, the team offers a new strategy to reverse the core symptoms of Parkinson's by reversing the activity inhibition in D1 spiny neurons in the specific brain regions. This is easily done in transgenic rodent model studies but the method had limited therapeutic meanings for it was hard to apply on primate brains. The team solved the problem utilizing a retrograde AAV capsid that can effectively infect axons of selected projection neurons, delivered to the substantia nigra pars reticulata. These retrograde AAVs then infect the axons and label D1 spiny neurons, while the axons of D2 spiny neurons extend into the paleostriatum, preventing the possibility of labeling. This D1 spiny neuron-targeted labeling strategy, coupled with chemogenetic-mediated neural activity modulation, allows for selective activity control of D1 spiny neurons/direct pathway in the primate brain. This enables targeted intervention for the motor symptoms of Parkinson's disease.
The method actively resolve the clinical translation from rodents to NHP to human. As a NHP specialized CRO, we have developed stable and potent NHP disease models and techniques to dissect, target, and modulate specific neural circuits for therapeutic purposes will greatly increase so research like this can be better carried out and transformed smoothly into clinical practice.
Reference
Chen Y, Hong Z, Wang J, Liu K, Liu J, Lin J, Feng S, Zhang T, Shan L, Liu T, Guo P, Lin Y, Li T, Chen Q, Jiang X, Li A, Li X, Li Y, Wilde JJ, Bao J, Dai J, Lu Z. Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model. Cell. 2023 Nov 22;186(24):5394-5410.e18. doi: 10.1016/j.cell.2023.10.004. Epub 2023 Nov 2. PMID: 37922901.
