In the fight against Sanfilippo syndrome and other similar genetic conditions, one of the most promising treatment options being trialled is gene therapy. However, there is a problem that can limit the use of gene therapy and means many otherwise eligible patients can miss out.
Researchers led by Associate Professor Haiyan Fu at the Gene Therapy Centre, University of North Carolina, United States, have recently published research showing that it may be possible to overcome this problem and improve the success of gene therapy for Sanfilippo syndrome. Their paper was published in the prestigious journal Nature
One of the most common ways to deliver gene therapy is using a non-replicating virus. The therapeutic gene, usually a healthy version of the gene that is damaged in individuals with a genetic disease, is packaged into the virus and the virus carries the gene to the cells where it is needed (read our background article on gene therapy here for more information).
Adeno-Associated Viruses (AAV) are frequently used for this purpose, however, many people have previously been exposed to these common viruses and their immune systems have generated antibodies that recognise and attack the virus, preventing the therapy from working.
The research team investigated whether a product called IdeS could deplete these antibodies and increase the chance of success of gene therapy in a mouse model of Sanfilippo syndrome. IdeS is a molecule derived from the bacterium Streptococcus pyogenes, that cleaves immunoglobulin G (IgG) proteins, the proteins that antibodies are made of.
They first modified the IdeS molecule and tested different versions of it in cells to optimise the IgG-cleaving ability of the product. They found promising results with all IdeS products, however one version, called IdeSop2, showed the best results and was taken forward for testing in mice with Sanfilippo syndrome type A.
To mimic the naturally occurring antibodies against AAV that are found in some humans, the mice were injected with AAV9-IgG antibodies from rabbits. Half the mice then received the IdeSop2 product and half did not receive the IdeSop2. The team found that there was a rapid reduction in AAV9-IgG antibodies 4 hours after treatment with IdeSop2 and the number of antibodies in the serum continued to reduce over the course of 24 hours.
These results indicated that IdeSop2 treatment at an effective dose of 0.45 mg/kg can rapidly deplete high levels of existing AAV9 antibodies found in the body.
The research team then looked at how effective the IdeSop2 treatment was when used in conjunction with an AAV gene therapy called scAAV9, in mice with type A Sanfilippo syndrome. They found that when IdeSop2 was combined with the gene therapy treatment in mice with pre-existing AAV9 antibodies, the gene therapy was as effective as it was in mice without pre-existing antibodies. They saw the same significant reduction in the amount of glycosaminoglycans (GAG) in tissue and brain samples taken from the mice that mirrored the normal levels seen in mice without Sanfilippo syndrome.
With further research, the team are hopeful that in the future this treatment option may be available for use in individuals with Sanfilippo who would previously have been ineligible for AAV gene therapy due to their pre-existing immunity to the gene therapy vector.
Thank you to volunteer guest writer, Hollie Rowland, for her contribution to this article.