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Palfi S, Gurruchaga JM, Ralph GS, Lepetit H, Lavisse S, Buttery PC, Watts C, Miskin J, Kelleher M, Deeley S, Iwamuro H, Lefaucheur JP, Thiriez C, Fenelon G, Lucas C, Brugières P, Gabriel I, Abhay K, Drouot X, Tani N, Kas A, Ghaleh B, Le Corvoisier P, Dolphin P, Breen DP, Mason S, Guzman NV, Mazarakis ND, Radcliffe PA, Harrop R, Kingsman SM, Rascol O, Naylor S, Barker RA, Hantraye P, Remy P, Cesaro P, Mitrophanous KA. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet. 2014 Mar 29;383(9923):1138-46. Epub 2014 Jan 10 PubMed.
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The study by Palfi et al. is a welcome addition to the literature, reporting the results of 15 Parkinson’s patients treated with a lenti-viral vector intended to enhance dopamine function in the terminal field of the degenerating dopamine neurons. The trial, launched in 2008, is an uncontrolled, open-label, dose-escalation safety study and the first reporting the use of a lenti-viral vector for a neurological disease. Described as a Phase 1/2 trial, this study does not differ substantially from past dose-escalation gene therapy Phase 1 safety studies in Parkinson’s, rendering the Ph1/2 distinction more a semantic preference than a representation of substantial difference in study design. The safety profile is encouraging, with most adverse events being mild and deemed unrelated to treatment. Thus, the data from this trial build on an impressive safety record for gene therapy in neurological diseases, now involving nearly a dozen clinical trials and scores of treated subjects (mostly in Parkinson’s and Alzheimer’s), spanning a decade. Collectively, these trials demonstrate that the major safety hurdles previously suppressing CNS gene therapy have been solved, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, several of those studies also demonstrated controlled, highly persistent generation of biologically active proteins, selectively targeted to structures deep in the human brain. The modest efficacy improvements reported in the current Palfi et al. Lancet paper are comparable to those reported in many prior open-label gene therapy Parkinson’s studies; importantly double-blind, controlled studies of those treatments could not adequately differentiate between treatment and placebo. The Palfi data therefore further emphasize the difficult nature of producing robust effects in the later stages of Parkinson’s disease. Indeed, the authors concluded that they will not conduct a more definitive double-blind placebo-controlled trial until “we have an optimal mode and dose of delivery," thereby acknowledging the unfortunate reality that a more robust response is required that presumably will require further iterations to the product, its dosing, and possibly clinical design.
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