By: David Warmflash
Despite being one of the most difficult organs to reach with drugs and surgery, the brain is one of the best places to tinker with gene therapy. Neurosurgeons are well practiced at injecting therapeutic agents and placing electrodes into specific brain areas, including areas of the basal ganglia that are important in Parkinson disease. Using the same technologies that allow precise location of instruments in the brain for various procedures, neurosurgeons can place catheters to inject vectors carrying genetic material for delivery into cells in specific brain regions. The ease of doing this is one reason why the brain is a site of early gene therapies.
Another reason is why gene therapy is being pioneered specifically in the brain is that immune response to injected agents is generally less compared with immune responses in other parts of the body. But the risk of such a response is not zero. Even in the brain, it’s possible that a gene-carrying vector can provoke an immune response, leading to failure of the treatment and potentially fatal complications. For this reason, one major factor influencing selection of a vector to carry a therapeutic gene in the setting of Parkinson disease is the vector’s immunogenicity and its ability to provoke an immune response. However, there are other major deciding factors. One factor is payload capacity—how much therapeutic genetic material each vector particle can carry in addition to other genetic material that has to be in there to enable the vector to get the genetic material into the target cells. Another deciding factor is whether the vector delivers the payload such that it integrates into the target cell chromosomes, or simply exists as an episome, producing gene product but not inserting into the main nuclear genome.
In part I, we noted that Phase 1 clinical trials have been successful using a vector adenoassociated virus (AAV) to provide cells of the putamen with the gene for aromatic amino acid decarboxylase (AADC), the enzyme that converts the levodopa to dopamine. In phase 1, success means that the treatment appears to be safe at the tested doses. As with a drug, the dose of gene-carrying vectors matters not just for strength of the therapeutic effect, but also with undesirable effects such as immunogenicity. Each AAV particle can carry only one copy of the AADC gene, so the amount of vector particles that can be delivered will be the limiting factor for how many cells in the target area can receive a gene (some cells will get lucky and get more than one gene, causing more dopamine production, but what matters is how many gene copies get delivered into cells overall); thus, as clinical studies progress through phases 2 and 3, researchers will be concerned most with a tradeoff between how much vector can be delivered versus increased risk of an immune response with higher vector doses.
How Long Will Effects Last?
While creating such episomes minimizes the chances of mutagenesis and thus the long-term risk of cancer, the effects could also end up being temporary. While phase 1 studies are looking at a decrease in Parkinsonian symptoms as a secondary endpoint, the focus is still on safety, and it could be years before it is clear how long the treatments last. Treatment effects may prove to last for many years, or decades, or there could be loss of episomes or degeneration of cells that successfully absorbed the gene.
In the latter case, we could end up in a scenario akin to that of vaccines, in which patients need follow-up booster treatments every certain amount of years, but that really wouldn’t be so bad. After all, if the rapid development of gene therapy over the last two decades is any indication, chances are that stalling a neurodegenerative condition by even just a few years will put patients in an excellent position to be helped by still newer treatments. The message of this series, that we can now deliver molecular therapies safely into the brain, is just the beginning. In the years to come, the advances will involve the particular genetic content of the therapies. Some of that genetic content is on the horizon—in vivo line-item gene editing using CRISPR-Cas technology, in particular, could potentially lead to another sea change in the world of gene therapy.