Gene therapy for nervous system disorders

My decision to get involved with developing gene therapy for neurological disorders came about because my own daughter, Ornella, 11, was born with a rare genetic condition known as Sanfilippo Syndrome, or mucopolysaccharidosis (MPS-IIIA). One in 70,000 babies is born with this life-limiting condition that results from a genetic mutation of a particular enzyme and leads to toxic build-up of heparan sulphate in brain tissue. Heparan sulphate is necessary for the normal function of the brain, but too much can damage tissue.

At present, there is no cure, treatment is palliative and sufferers die in their early teens. Symptoms range from mild developmental delay and hyperactivity, which leads to sleep disturbance to more profound problems, such as paralysis, usually before the child reaches his or her 10th birthday.

Five years ago, Ornella became the first person in the world to have an experimental new drug treatment that we are developing at Lysogene, the biotech company I founded with Olivier Danos, a leading researcher into neurodegenerative disease. He had already been looking into this area of research and was keen to look at novel approaches.

She was part of a Phase 1/2 clinical trial that took place in 2011 and 2012 to gauge the safety of gene therapy using an adeno-associated viral vector known as AAVrH10 to deliver a genetically modified N-sulfoglucosamine sulfohydrolase enzyme directly into the brain cells. This enzyme effectively mops up the excess heparan sulphate and disposes of it. Animal studies had already shown it was safe and effective. The four children involved ranged in age from just under 3 years old to just under seven years old and they were dosed individually, one after the other, over three month intervals. The vector is injected into areas of the brain that  show signs of damage during an operation under  general anesthesia

AAVrH10 is a viral vector that is able to move into brain cells more efficiently where it delivers the drug. Other AAV vectors have been investigated by other research teams but with less effective uptake of gene therapy in the brain. All AAV vectors are very safe and stable so they are long-lasting. They also seem to cause no harmful effects in brain tissue.

This is a very elegant solution to a problem that is very localised in MPS-IIIA patients. The vector delivers the drug directly to the neurons where it is needed. It is also a once-only therapy because it fixes the faulty DNA of the enzyme permanently. Sadly, many children with genetic diseases need to have regular therapy, which often requires a hospital visit several times a month. This kind of gene therapy should mean that there is no need to repeat it more than once.

I’m glad to say that the trial, which only included human patients with advanced disease, was a success and the results were published in Human Gene Therapy in 2014. As well as being safe, the therapy resulted in reduction in symptoms and a big increase in quality of life. Ornella showed tremendous improvement and started sleeping through the night – something that had never happened from the day she was born until she was treated at six years old. We are hopeful that the therapy may also have the ability to extend life for patients with this disease. Certainly, this is what we observed in early animal studies. Potentially, it may even be curative.

Without such promising results, there was no way that I could consider continuing with the research programme. If I had not been convinced of its efficacy and safety, I would have called a halt after the initial trials.

We are now preparing to embark on a larger scale Phase 3 clinical trial with 20 patients in all. This will take place in 2018. If all goes well, we hope to market the drug to patients by 2020. I feel really blessed and proud to be involved in such an important project and to part of such a great team at Lysogene.

Karen Aiach is speaking at the RSM Medical Innovations summit on April 22nd. www.rsm.ac.uk