Objective: Develop a sustained disease modifying gene therapy for treating Parkinson’s disease

Background: Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, which leads to reduced dopamine levels in the striatum and the hallmark motor symptoms of the disease ^[1]. Conventional treatment with levodopa helps replenish dopamine but loses efficacy over time due to the diminishing capacity of the brain to convert levodopa to dopamine ^[2].

AADC is responsible for converting levodopa into dopamine ^[3]. GDNF is a neurotrophic factor known to promote the survival, growth, and regeneration of dopaminergic neurons ^[4].

We have developed VGN-R09b, an AAV9-based AADC and GDNF combination gene therapy that is delivered to the striatum via brain parenchymal injection for treating PD. The AADC would enhance dopamine levels to boost dopaminergic transmission and improve motor function. While GDNF would exert its neuroprotective effects to potentially slow or halt disease progression.

Method: Preclinical efficacy studies: VGN-R09b was injected to the striatum of 6-OHDA-induced PD mouse and rat models. The rotational behaviors in response to apomorphine and low-dose L-DOPA were then recorded and analyzed.

Toxicology studies: A GLP toxicity study of VGN-R09b was conducted in cynomolgus monkeys through a single bilateral intraputaminal infusion.

Phase 1 clinical study: Phase 1 registration study of VGN-R09b in PD patients has completed administration of the first dose group in 3 subjects (1 female and 2 males), whose ages at enrollment were 51 to 56 years old. They received bilateral local injections of the drug at a dosage of 8.0×10^11 vg.

Results: Preclinical efficacy studies in two rodent PD models demonstrated that intra-striatal injection of VGN-R09b dose-dependently improved motor impairments, enhanced L-DOPA responsiveness, and protected dopaminergic terminals of PD animals. Toxicology studies of VGN-R09b revealed a favorable safety profile and identified human starting dose. In a Phase 1 clinical study, VGN-R09b was well tolerated with no AE observed and has improved the motor scores and the daily “on” and “off” time in study subjects.

Conclusion: Efficacy and safety results from preclinical and preliminary clinical studies showed that VGN-R09b, an AADC and GDNF combination gene therapy is a promising novel treatment for PD.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

References: [1] Kouli, A., K.M. Torsney, and W.L. Kuan, Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis, in Parkinson’s Disease: Pathogenesis and Clinical Aspects, T.B. Stoker and J.C. Greenland, Editors. 2018: Brisbane (AU)
[2] Zahoor, I., A. Shafi, and E. Haq, Pharmacological Treatment of Parkinson’s Disease, in Parkinson’s Disease: Pathogenesis and Clinical Aspects, T.B. Stoker and J.C. Greenland, Editors. 2018: Brisbane (AU)
[3] Bankiewicz, K.S., et al., Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC. Mol Ther, 2006. 14(4): p. 564-70; Christine, C.W., et al., Magnetic resonance imaging-guided phase 1 trial of putaminal AADC gene therapy for Parkinson’s disease. Ann Neurol, 2019. 85(5): p. 704-714
[4] Nasrolahi, A., et al., Neurotrophic factors hold promise for the future of Parkinson’s disease treatment: is there a light at the end of the tunnel? Rev Neurosci, 2018. 29(5): p. 475-489

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/vgn-r09b-an-adeno-associated-virus-based-combination-gene-replacement-therapy-for-parkinsons-disease/