Can delivering the DNA lead better drug discovery models? Our ongoing coverage from the Society for Neuroscience meeting

Adeno-associated viruses (AAVs) have shown promise as gene-therapy delivery vehicles in clinical trials evaluating a potential cure for hemophilia and a genetic form of blindness. They are also being used to aggressively in preclinical studies to pursue new treatments for Parkinson’s disease by going after a brain protein considered to be the key driver of the disease.

That driver is alpha-synuclein (α-syn), a common brain protein that goes rogue in the brains of people with PD. Fibril clumps of abnormal α-syn gradually accumulate in their brains and eventually, scientists believe, throw off the cells that produce dopamine—a brain chemical critical to movement—from working properly.

AAV viral vectors are already an important player in human gene therapy trials studies of PD. An AAV vector carrying a gene that promotes the expression of an enzyme in PD patients helped improve motor function, a recent study found.

But AAV and other viral vectors are also immensely useful in helping us to model the disease in rodents. While current treatments are aimed at replenishing dopamine levels, none are able to restore the lost cells. By delivering disease-causing mutations of α-syn to dopamine regions in the brain, we can gain new insights about the biological mechanisms that lead to PD. And because these models are able to reliably produce changes in the brain similar to PD, we can also use them to test drug candidates that might make a bigger impact.

“By using AAVs we can target genes of interest,” says Antti Nurmi, Managing Director of the Charles River Discovery site in Finland, which specializes in CNS disorders. “A typical example of that would be to introduce an AAV vector closer to dopamine to transfect [cells that release dopamine] so that they start expressing abnormal alpha synuclein.”

Yet because so many different laboratories are experimenting with this viral vector model we now have created a plethora of inconsistent results. It is also challenging to find ways of measuring movement dysfunction in the these models because when you can detect changes in the brain consistent with PD, it is not always possible to notice a telltale sign of PD. Three papers presented at the Society for Neuroscience meeting in Washington, DC by scientists from Charles River and their commercial partners offer some clarity to these questions by showing that not every species is capable of mounting an acceptable response against the AAV models and that newer generation analytic methods of clocking movement in animals may be the way to go.

Charles River’s collaborators on the study included Merck, Pfizer, Atuka and the Michael J. Fox Foundation. Among the key

  • Scientists have traditionally used the rotarod—the equivalent of a mouse running on a wheel—to measure coordination in CNS models. But fine motor kinematic analysis, which detected subtle changes in multiple rat models following α-syn delivery, appears to be a more reliable method of tracking changes in movement. Kinematic analysis is more high-tech and for early signatures of certain neurodegenerative disorders uniquely valuable. Scientists first angle a high-speed camera simultaneously from three dimensions to capture the mice on film and then analyze their movements with kinematic algorithms—a kind of geometry of mice in motion. Charles River has been documenting kinematic analysis in Huntington’s disease mice for over four years, as well as amyotrophic lateral sclerosis and stroke. In this recent study, three different rat models following α-syn deliver demonstrated significant changes in movement, confirming the value of this behavioral tool in drug discovery studies.
  • Multiple rodents, more options? Earlier studies have shown that delivering AAA viral vectors to rats is a useful model for studying new drugs. Rats develop characteristics associated with PD, including loss of dopamine neurons, motor impairment and neuro-inflammation. But it turns out at least two species of mouse are also a viable option. The fine motor skills were significantly affected following delivery of the α-syn. They also exhibited reductions in an enzyme that affects dopamine levels. However results in the various mouse models were not consistent across the board – some responded better than other to the delivery of α-syn—underscoring the importance of selecting the proper strain in AAV studies.
  • And if you are using rats, select the proper strain. Studies in multiple rat models found one was highly sensitive to delivery of α-syn, while another had only a minimal response.