A potentially revolutionary and “exciting” therapy for a rare brain disease has shown promise prior to a clinical trial, an international conference has heard.
Sanfilippo’s disease type A – or mucopolysaccharidosis type IIIA (MPSIIIA) – causes a progressive loss of developmental skills in young children. It is caused by a germline mutation in the SGSH gene, which results in a lack of the sulfamidase enzyme. This leads to an accumulation of mucopolysaccharides inside cells, which leads to progressive cognitive impairment and other symptoms. Intravenous enzyme replacement therapy has proved ineffective so far, as sulfamidase cannot cross into the brain from the blood.
Professor Brian Bigger from the University of Manchester revealed that the safety and feasibility of an investigational gene therapy for Sanfilippo’s disease is becoming clearer, as a formal clinical trial gets underway. He presented the work at the American Society of Gene & Cell Therapy annual meeting in April.
The treatment involves harvesting patient’s blood stem cells, and then delivering the missing SGSH gene into to the blood stem cells in the laboratory with a lentiviral vector. The manufactured gene-modified stem cell product is then transplanted into the patient. The stem cells then regenerate the immune system, which means the patient has a working, and potentially permanent, copy of the gene.
The investigational gene therapy was delivered to a two-year-old under a special licence at The Royal Manchester Children’s Hospital in 2019 by Professor Rob Wynn, following more than ten years of development and pre-clinical work at the university.
The patient was followed for a year after the treatment. Preliminary results have revealed rapid engraftment of the gene modified cells, and led to amounts of the enzyme in the blood that were more than 25-fold the median normal levels.
At six months after treatment, levels of SGSH enzyme in cerebrospinal fluid were at the upper end of normal range.
Prof Bigger said: “These results are promising and provide some hope for these children whose condition was previously thought to be incurable. The trial is the critical next stage, but it’s true to say we are excited.
“Sanfilippo disease is an appalling disease which causes misery to these children- so the prospect of a treatment is tantalising – especially when it was thought for years that no treatment would be possible.”
The team have now begun a phase I/II clinical trial for the therapy. Between three and five children, all aged under two years and who have severe MPSIIIA, will be given the gene therapy transplant.
The first patient was recruited to the trial in early January 2020 and their blood stem cells were harvested and modified prior to transplant back into the patient this month (May 2020). The child will be assessed over the next three years.
The trial is being sponsored by the University of Manchester and the gene therapy product is being manufactured at University College London Great Ormond Street Hospital Institute of Child Health using the expertise of Professor Adrian Thrasher’s specialist gene therapy laboratories.
Source: University of Manchester - https://www.manchester.ac.uk/discover/news/brain-disease-treatment-shows-promising-signs/
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