Lentiviral gene therapy shows clinical benefit in macaque models of Parkinson’s diseasePublished: August 22, 2019
A pre-clinical study has demonstrated the safety and clinical efficacy of an experimental gene therapy, AXO-Lenti-PD (OXB-102), in non-human primate models of Parkinson’s disease. Findings from the study thus support an ongoing Phase 1/2 clinical trial being conducted in Parkinson’s patients.
Parkinson’s disease (PD) is a neurodegenerative disorder involving loss of neurons that release dopamine in the striatum. Preventive or long-term disease-modifying treatments are not currently available for PD. Oral dopamine replacement therapy is the standard treatment prescribed to patients to compensate for the loss of dopamine. However, as the disease progresses, these therapies become less effective and is associated with motor fluctuations, involuntary movements and other complications.
To address the complications associated with oral therapies, strategies aimed at providing a continuous and local restoration of dopamine to the striatum is required and gene therapy has emerged as an attractive tool for that.
ProSavin, one such lentiviral vector-based gene therapy for dopamine replacement, was evaluated in pre-clinical and clinical studies recently. Although the treatment yielded promising results in early clinical trials, data suggested that this gene therapy didn’t increase dopamine production enough for maximum benefit.
In the present study published in Molecular Therapy Methods & Clinical Development, researchers at Paris-Sud University in France investigated the safety and clinical benefit of another lentiviral-based gene therapy, AXO-Lenti-PD, in non-human primate models of PD. Like ProSavin, AXO-Lenti-PD gene therapy uses lentiviral vector to deliver a genetic payload that lets cells make more dopamine. But AXO-Lenti-PD uses an optimized expression cassette to get the most dopamine production possible.
The therapy was administrated surgically directly into the brain of the MPTP macaque model of PD. The monkeys were treated with either a high or low dose of AXO-Lenti-PD, or with ProSavin (positive control; developed by Oxford Biomedica) or a control vector.
Data showed that, compared to animals in the control group, those given the active gene therapy displayed fewer parkinsonian symptoms at 3- and 6-months post-treatment. Animals that received the high dose of AXO-Lenti-PD had higher motor scores than the ProSavin-treated animals at the two time points tested.
Furthermore, assessment of the macaques’ brains suggested that those treated with either dose of AXO-Lenti-PD produced significantly higher levels of aromatic L-amino acid decarboxylase (AADC, an enzyme that helps in the production of dopamine) than those treated with ProSavin. The highest AADC expression was found in the high-dose AXO-Lenti-PD group, suggesting that this group had the most dopamine production.
The treatment was safe and well-tolerated by the animals. Findings from the study thus clearly demonstrate that AXO-Lenti-PD is both safe and effective. The study supports the clinical evaluation of this therapy in PD patients which is now underway in England and France (SUNRISE-PD trial).
AXO-Lenti-PD is developed by Oxford Biomedica and Axovant. Early clinical date has shown that a single dose of AXO-Lenti-PD was well-tolerated and improved motor function after six months in two people with advanced PD.
Source: Gene Therapy for Parkinson’s Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis. Badin RA et al., Molecular Therapy Methods & Clinical Development, August 2019. DOI