An investigational gene therapy for a syndrome that leads to a form of childhood dementia has shown promising early results in a proof-of-concept study, a conference will hear today.
The study into Sanfilippo syndrome by researchers at Manchester University NHS Foundation Trust, UK, found after being given OTL-21, an investigational gene therapy, four out of five patients gained cognitive skills in line with development in healthy children.
While the results are positive, researchers will tell delegates to the WORLD Symposium™2023 on Lysosomal Diseases, today, that caution is needed because most of those patients were not yet four or five years old, which is when the most severe stages of disease progression tend to present.
For the trial, patients were six to 24 months of age when they were given OTL-201, and the preliminary results are based on a median follow-up of two years. Trial participants will be followed for a minimum of 36 months.
Sanfilippo syndrome Type A – also called Mucopolysaccharidosis Type IIIA (MPS-IIIA) – is a genetic disease of the central nervous system.
It affects about 1 in 70,000 children, all of whom have a mutation in the SGSH gene, which means they lack an enzyme that breaks down large sugar molecules.
These molecules accumulate in the cells, causing irreparable damage to many organs, including the brain, which leads to inflammation and damage to brain tissue.
In this trial, researchers collected participants’ own blood stem cells and inserted a working copy of the SGSH gene using a lentiviral vector before the cells are put back. This enables patients to make this missing SGSH enzyme.
The results showed an improvement in neurocognitive assessments compared with natural progression of the disease in one of the children at 18-months post-treatment.
Three additional patients are within the normal cognitive development range at 9 to 18 months post-treatment, but require longer follow-up to assess outcomes, and after a median of two years, OTL-201 which was generally well tolerated in all the patients.
The trial also found that higher amounts of the SGSH enzyme were seen than would be normally found in the blood and cerebrospinal fluid of healthy children.
Professor Brian Bigger, chair in cell and gene therapy at the University of Manchester, who carried out the preclinical work said: “We have been hopeful this therapy will be transformative for patients- and these early results are very encouraging – but there’s still a long way to go.
“Importantly, the safety profile of the investigational therapy is currently considered favourable in these patients, with the lentiviral vector reporting a polyclonal pattern of integration, and blood stem cells engrafting and producing cells in the blood system which are able to make the missing enzyme in patients.
“The human monocyte-specific promoter in the lentiviral vector was designed to have a very low risk of causing insertional mutagenesis – the accidental switching on of genes causing cancer. This is critical for the future safety of the patients and the developmental potential of this therapy.”
Professor Robert Wynn, chief investigator on the trial at The Royal Manchester Children’s Hospital, added: “These are encouraging results for children living with MPS-IIIA and their families, who currently have no effective treatment options.
“In addition to sustained engraftment of gene-corrected cells and supraphysiological SGSH enzyme levels in the periphery, the early neurocognitive findings show most patients are gaining skills in line with the development of healthy children. In one patient, we also have seen a marked improvement from disease natural history, and we hope to see similar results in the other patients with longer follow-up.”
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