Gene Therapy for Parkinson’s Disease: Preclinical Evaluation of Optimally Configured TH:CH1 Fusion for Maximal Dopamine Synthesis

• Published in: Molecular therapy. Methods & clinical development Vol. 14; pp. 206 - 216
• Main Authors: Badin, Romina Aron, Binley, Katie, Van Camp, Nadja, Jan, Caroline, Gourlay, Jeanne, Robert, Camille, Gipchtein, Pauline, Fayard, Audrey, Stewart, Hannah, Ralph, G. Scott, Lad, Yatish, Kelleher, Michelle, Loader, Julie, Hosomi, Koichi, Palfi, Stéphane, Mitrophanous, Kyriacos A., Hantraye, Philippe
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13-09-2019; Elsevier Limited; Cell Press; American Society of Gene & Cell Therapy
• Subjects: Amino acids; Animals; Basal ganglia; Biosynthesis; Central nervous system diseases; Clinical trials; Dopamine; Dopamine receptors; dopamine replacement; Enzymes; Gene therapy; Immune response; lentiviral vector; Life Sciences; Locomotor activity; Lymphatic system; Monkeys & apes; Movement disorders; MPTP; MPTP primate model; Neostriatum; Neurodegenerative diseases; Parkinson's disease; Positron emission tomography; Primates; Toxicology; United Kingdom > UK; Singapore; gene therapy; dopamine replacement; MPTP primate model; Parkinson’s disease; lentiviral vector
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2019.07.002

A recent phase I-II, open-label trial of ProSavin, a lentiviral vector delivering the key enzymes in the dopamine biosynthetic pathway to non-dopaminergic striatal neurons, demonstrated safety and improved motor function in parkinsonian patients. However, the magnitude of the effect suggested that optimal levels of dopamine replacement may not have been achieved. OXB-102, a lentiviral vector with an optimized expression cassette for dopamine biosynthesis, has been shown to achieve a significantly higher dopamine yield than ProSavin. We assessed the efficacy of OXB-102 in the MPTP macaque model of Parkinson’s disease (PD). At 6 months post-vector administration, all treated animals showed significant improvements in clinical scores and spontaneous locomotor activity compared to controls, with the highest recovery observed in the OXB-102 high-dose (HD) group. Positron emission tomography quantification of 6-[18F]-fluoro-L-m-tyrosine uptake showed a significant increase in amino acid decarboxylase activity for all treated animals, compared with controls, where the OXB-102 HD group showed the highest level of dopaminergic activity. A toxicology study in macaques demonstrated that the vector was safe and well tolerated, with no associated clinical or behavioral abnormalities and no immune response mounted against any transgene products. Overall, these data support the further clinical development of OXB-102 for the treatment of PD.