By: David Warmflash
In the previous post, we discussed Parkinson disease as a gene therapy candidate with emphasis on the idea that standard therapies, while initially very helpful, lose effectiveness over time as affected brain areas degenerate.
When it comes to movement control, basal ganglia pathways are similar to an autopilot system, but not the kind of autopilot that can be turned off when malfunctioning in a simple aircraft. Rather, the pathways are like computer controlled systems of a complex aircraft that the pilot cannot fly manually. When dopamine is deficient—or when there’s a low ratio of dopamine versus another neurotransmitter called acetylcholine—a chain of events shifts automatic movement control from what’s called the direct pathway to a cruder circuit called the indirect pathway. Think of it as a secondary, cruder computer system taking over when the primary autopilot cuts out. The rudder and ailerons still work, but not with the usual finesse. The aircraft starts shaking and the pilot has to work harder to keep flying straight.
An analogous thing happens in Parkinson disease, but instead of shaky flying, it manifests as bradykinesia/hypokinisia (slow movement), tremors, rigidity, pill rolling, festination (taking fast, tiny steps while walking), and shaky voice. These are classic, notorious Parkinsonian symptoms, and can be tracked to degeneration of dopaminergic cells in a part of the basal ganglia called the substantia nigra. Axons run from the substantia nigra to another basal ganglial area, the striatum, and specifically, a striatal region called the putamen. This is the target for a particular category of Parkinson gene therapy, namely therapy with the gene for aromatic amino acid decarboxylase (AADC), the enzyme that converts the levodopa to dopamine.
Supplying the AADC gene is one of three main strategies that look promising in gene therapy research. Normally, the AADC enzyme that’s made by the gene is used in niagral cells to convert levodopa (L-dopa) into dopamine. Those cells degenerate in Parkinson disease, but the normal target on their dopamine is the putamen, so that’s also the target for delivering the AADC gene. Once functioning in putamen cells, a transplanted AADC gene will enable those cells to make their own dopamine from L-dopa, so they can function normally again without depending on the niagral cells that no longer function.
For episomal gene delivery of AADC, Voyager Therapeutics has built up expertise with a vector known as adenoassociated virus (AAV). Several AAV subtypes exist, one of which lends itself particularly well for delivering payload to the brain, liver, and some other tissues. A drawback of AAV is that it’s small, so the AADC gene fits in with barely any room to spare. There are larger vectors available, but the tradeoff is that they tend to carry a higher risk of immunogenicity.
The ability to deliver its genetic payload as an episome, rather than integrating the delivered gene into the patient’s chromosomes, is an added safety feature of the AAV vector (along with the reduced immunogenicity compared with other vectors). However, there’s a potential disadvantage of episomal delivery that we’ll discuss in the next and final post of this series, which will discuss the issue of why the brain, of all places, makes such a good target for gene therapy.