Zhonghua Lu, Investigator, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences

Title:
Development of nonhuman primate models and therapeutic strategies for neurodegenerative disorders

Abstract:
Parkinson’s disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but their action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and the periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient novel retrograde AAV, promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.

In a second study, we have generated PSEN1 mutant cynomolgus macaques (PSEN1-ΔE9) through the genomic deletion of PSEN1 exon 9. Whole-genome sequencing and genotyping analyses of somatic cells confirmed the ΔE9 mutation at both the DNA and transcript levels, with minimal off-target effects. Fibroblasts derived from newborns exhibited signatures of familial Alzheimer’s disease (AD) pathogenesis, including disrupted PSEN1 endoproteolysis, resulting in the presence of full-length PSEN1 protein and an increased beta-amyloid (Aβ)_42/40 ratio. Furthermore, blood transcriptome profiling of mutant macaques revealed molecular dysregulation associated with AD.