Much of our research over the year has been focused on further development of viral vector technologies to deliver gene-modifying cargoes to enable axon regeneration after spinal cord injury. In consideration of eventual therapeutic application, we’ve continued to assess how knocking down PTEN for long periods of time affects nervous system function. The reason is that vector-based strategies to knock down PTEN to enable regeneration aren’t like drugs that you can stop taking; the vectors remain active for months and the gene cargoes they carry continue to be expressed.
The good news is that we’re continuing to find that long-term vector-mediated knockdown of PTEN in the way that enables regeneration doesn’t have major negative consequences. In early 2020, we published a major pap per in the scientific journal Experimental Neurology in which we show that deleting PTEN in the cortex doesn’t cause any abnormal brain activity such as seizures (https://doi.org/10.1016/j.expneurol.2019.113098). We did find that some intracellular signaling pathways involved in synaptic plasticity were altered in neurons lacking PTEN. This may mean that functional benefits of regeneration due to PTEN knockout might be enhanced by restoring PTEN expression after regeneration has been achieved.
Another major paper that has just been accepted in the scientific journal Cerebral Cortex is our first study using the amazing new technology of retro-AAV. This paper is the first report in a scientific journal of what we told you about in our fall newsletter last year (Anatomy 101, Spinal connections Number 32). The main take-home is that injections of retro-AAV into the spinal cord lead to the delivery of gene-modifying cargoes to the majority of nerve cells in the cortex that give rise to the corticospinal tract. We’re just completing several studies to test whether this approach leads to even more recovery than is seen with deletion of PTEN by injecting AAV into the cerebral cortex.
Finally, we are continuing to focus a major part of our effort on studies of possible therapies for chronic spinal cord injury, what we call the Chronic Injury Project. One example is testing whether targeting PTEN can induce regeneration and recovery in the chronic injury setting. As you can imagine, these studies take a long time to complete and are very expensive because the first step is to create spinal cord injuries in rats and then maintain the animals for months until the injuries are chronic. It’s very difficult to get funding from NIH for such long-term studies because the work goes slowly and grant reviewers like experiments that get quick results. We are extremely grateful to Bob Yant and his company, Cure Medical, for their extremely generous donations to support the Chronic Injury Project.