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By: David Warmflash

Thirty years ago, the idea of gene therapy wDavid Warmflashas science fiction. But today many challenges have been overcome, particularly for medical conditions that lend themselves well to genetic manipulation.

Parkinson disease is one such case. The pathophysiology is immensely complex, but the condition can be treated via a handful of pharmacologic agents or by stimulation of certain brain areas with surgically placed electrical probes.

Standard therapies are helpful initially but lose effectiveness over time as affected brain areas degenerate. In recent studies, stem cell strategies and injection of growth factors and the enzyme aromatic L-amino acid decarboxylase (AADC, which cells use to convert L-DOPA to dopamine) has shown promise, but it also has some limitations. However, research over the last several years has honed in on a handful of gene and pathway choices to optimize therapy for Parkinson disease, and one particular method for delivering selected genes.

Choosing Therapeutic Genes

One gene therapy approach to Parkinson disease uses the AADC gene, encoding the AADC enzyme. Normally, this enzyme is used in substantia nigra cells to supply dopamine to receptors in the putamen. In AADC gene therapy, the gene is supplied instead to putamen cells, so they can make their own dopamine and function without depending on the failing niagral cells. The main issues of phase 1 clinical trials (spearheaded by Voyager Therapeutics) has been to deliver AADC into target tissue and to do so without causing further harm. Thus far, the therapy has proved promising and works because of advances in gene delivery that function particularly well for certain body tissues, including the brain.

Another approach is to deliver a gene for the enzyme glutamic acid decarboxylase (GAD) to another basal ganglial spot called the subthalamic nucleus. Alternatively, the genes could be delivered to the degenerating niagral cells to stop the degeneration process, with current attention on genes for growth factors, specifically glial cell line-derived neurotrophic factor (GDNF) and a similar protein called neurturin.

Episomal Delivery: Since random integration into chromosomes carries a high risk for mutagenesis, researchers deliver genetic payload as an extra-chromosomal element known as an episome. The transplanted genetic sequence is read by the cell’s translational machinery, leading to the enzyme product, but is separate from the cell’s chromosomes.

Choosing a delivery vector: For episomal delivery of all of the genetic payloads mentioned above, clinical researchers have been using 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.

Accessing the target tissue in the brain: 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 specific brain regions. The ease of doing this is one reason why the brain is a site of early gene therapies, but another reason is that the immune response to injected agents is generally less compared with immune responses in other parts of the body.

Clinical Trials

Phase 1 clinical trials have focused on demonstrating safe utilization of AAV as a vector to deliver the AADC gene as well as the GAD gene into the brain. Response of the patient’s immune system to the vector has always been a major issue in gene therapy. However, by working out the tolerance to different vectors, it may be possible to time steroid treatment into protocols that thwart immune responses. Because somewhat more work has been done with AADC strategy, we’ll focus on this gene in the next two posts, where we’ll delve into how the gene fits into the molecular physiology of the brain’s basal ganglia, and why the brain actually turns out to be one of the best targets for gene therapy.

David Warmflash, M.D., is an astrobiologist, science writer, and physician. He is principal investigator on a Planetary Society-sponsored investigation of the effects of the space environment on organisms.