Several Phase I gene therapy studies have been conducted for Parkinson’s disease using either lentiviral vectors (Prosavin) or adeno-associated vectors. Due to the fact that vectors are injected into the brain, it is not feasible to assess efficiency and duration of gene expression in patients. In a paper published last month, Sehara et al. 2017 showed that gene expression persisted for 15 years in a non-human primate model of Parkinson’s disease.
In addition, the study implied that (a) the phenotypic recovery observed at early time-points after injection was preserved for 15 years and (b) demonstrated long-term safety. Although the data is encouraging, only 1 out of four animals was studied at this later time-point, which somewhat limits the conclusions that can be drawn. However, this study is yet another example of very long-term persistence of AAV-mediated gene expression, which puzzles and surprises the research community.
Why is AAV, which is sought to not integrate into the genome of transduced cells, able to maintain gene expression over such a long period of time?
Why is this episomal vector so stable?
Is the persisting expression due to vector integration into chromosomes?
These are all unanswered questions and difficult to study in humans. Unfortunately, Sehara et al do not appear to have assessed the AAV integration status in the current study, which is a missed opportunity.
Sehara, Y., et al. (2017). “Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson’s Disease.” Hum Gene Ther Clin Dev 28(2): 74-79.