South Australian researchers, led by Professor Kim Hemsley at Flinders University, have published work comparing two gene therapy delivery routes on their ability to reduce degeneration of the retina in Sanfilippo.
Located at the back of the eye, the retina works to capture light and send visual information to the brain. Cells in the retina called photoreceptors are critical for this, but people with Sanfilippo can lose photoreceptor cells and develop night blindness.
While it is hoped that gene therapy could prevent or reduce photoreceptor cell loss, few studies measure the impact on the retina following gene therapy in Sanfilippo.
In this work, the team examined the health of the retina in a mouse model of Sanfilippo type A given AAV9 gene therapy via intravenous injection (into the bloodstream via a vein) or injection directly into the cerebrospinal fluid (CSF; the fluid that bathes the nervous system).
Newborn mice received an injection, via one of the two routes, which either included the gene therapy or a ‘mock treatment’ control (i.e. no gene therapy). Doses for each delivery method were different but represented the typical doses for each method used in Sanfilippo clinical trials. After 20 weeks, the researchers analysed key markers of retinal health to see which delivery route led to better outcomes.
As expected, there was no activity of the sulfamidase enzyme in the retina of the Sanfilippo type A mice in the no-treatment groups. They also had a significant accumulation of heparan sulfate (HS), the complex sugar that builds up in the disease.
Interestingly, the team found that sulfamidase enzyme activity in the retina increased only with gene therapy delivered intravenously. Gene therapy via this delivery route also reduced HS in the retina to normal levels, while CSF delivery only partially reduced HS levels.
Intravenously delivered gene therapy completely prevented photoreceptor cell loss throughout the retina. While gene therapy via direct CSF injection prevented photoreceptor cell loss at the very back of the eye close to the optic nerve, cells closer to the inside of the eye away from the optic nerve were still lost. This included the loss of a type of photoreceptor cell important in night vision.
The data indicate that gene therapy delivered intravenously can treat more of the retina compared to direct CSF gene therapy injection. The researchers suggest this may be due to the way the AAV9 delivery vehicle, or the sulfamidase produced from the gene therapy, reaches the retina. Further studies are needed to confirm the results and the mechanism involved.
Importantly, while intravenous delivery led to better outcomes in the retina, general brain sulfamidase activity increased more following direct CSF injection. This is consistent with previous studies from this research group and others. These findings suggest a combination of different therapies or delivery methods may be needed to optimise outcomes in the brain and the retina.
Clinical trials of gene therapy, and other therapies targeting the root cause of the disease, should also measure retinal degeneration to better understand the therapy’s impact on the retina. Considering all symptoms, including those that affect the eyes and vision, will help to improve the overall quality of life for patients who can receive these therapies.
Funding from the study included an Australian Government NHMRC Grant and funding from the Lysosomal Diseases Research Unit at SAHMRI (South Australian Health and Medical Research Institute).
