Mixed Results in Animal Studies of Gene Therapy Targeting Axonal Regrowth
Researchers here attempted a combination gene therapy using BDNF and TrkB in order to provoke growth of axons in the mouse optic nerve and brain. The hope is to produce enough repair and regrowth to outpace for a time the disease process that causes damage. This seemed to have positive results in the optic nerve, but less so when applied to a mouse model of tauopathy. The regenerative medicine community might argue that sufficiently comprehensive regenerative will help, and functional recovery following treatment is a matter of the balance between degree of regeneration versus degree of harm caused by the disease process. It remains the case that addressing the causes of the condition may also be necessary to achieve positive results in patients.
A common feature of neurodegenerative diseases is disruption of axonal transport, a cellular process responsible for movement of key molecules and cellular 'building blocks' including mitochondria, lipids, and proteins to and from the body of a nerve cell. Axons are long fibres that transmit electrical signals, allowing nerve cells to communicate with other nerve cells and muscles. Scientists have suggested that stimulating axonal transport by enhancing intrinsic neuronal processes in the diseased central nervous system might be a way to repair damaged nerve cells. Two candidate molecules for improving axonal function in injured nerve cells are brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB).
Researchers have now shown that delivering both of these molecules simultaneously to nerve cells using a single virus has a strong effect in stimulating axonal growth compared to delivering either molecule on its own. They tested their idea in two models of neurodegenerative disease known to be associated with reduced axonal transport, namely glaucoma and tauopathy (a degenerative disease associated with dementia).
Glaucoma is damage to the optic nerve often, but not always, associated with abnormally high pressure in the eye. In an experimental glaucoma model, the researchers used a tracer dye to show that axonal transport between the eye and brain was impaired in glaucoma. Similarly, a reduction in electrical activity in the retina in response to light suggested that vision was also impaired. The gene therapy restored axonal transport between the retina and the brain, as observed by movement of the dye. The retinas also showed an improved electrical response to light, a key prerequisite for visual restoration.
Next, the team used transgenic mice bred to model tauopathy, the build-up of 'tangles' of tau protein in the brain. Tauopathy is seen in a number of neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. Once again, injection of the dye showed that axonal transport was impaired between the eye and the brain - and that this was restored using the viral vectors. The team also found preliminary evidence of possible improvement in the mice's short-term memory, but those results did not quite achieve statistical significance.
This seems like maybe the most difficult repair to make. So, it's encouraging that scientists are going after it now. May not work now, but whatever humans try, they eventually figure out & succeed.