Gene therapy for ‘childhood dementia’ shows promise

Genetic engineering

An investigational gene therapy for Sanfilippo syndrome – which leads to a form of childhood dementia – has shown promising early results in a proof-of-concept study. 

The study found that four out of five patients diagnosed with Sanfilippo have continued to gain cognitive skills in line with development in healthy children after being given the investigational gene therapy, OTL-201. 

However, the researchers urge caution as the majority of patients have not reached the age of four to five years where the most severe stages of disease progression typically present. 

The trial patients were six to 24 months of age at the time of administration of OTL-201, and the preliminary results are based on a median follow-up of two years (range: nine to 30 months). Patients enrolled in the trial will be followed for a minimum of 36 months during which time the study investigators will continue to report additional biochemical and clinical outcomes. 

The rare genetic metabolism disorder called Sanfilippo syndrome Type A- or Mucopolysaccharidosis Type IIIA (MPS-IIIA)- is a genetic disease with devastating effects on the central nervous system affecting around one in 70,000 children. 

Patients with MPS-IIIA have a mutation in the SGSH gene, causing them to lack an enzyme which normally breaks down large sugar molecules. These molecules then accumulate in the cells of the body causing irreparable damage to many organs including the brain, leading to inflammation and damage to brain tissue. 

The investigational gene therapy OTL-201 works by collecting a patient’s own blood stem cells and inserting a working copy of the SGSH gene using a modified virus, known as a lentiviral vector. The patient’s modified blood stem cells, now including a working copy of the SGSHgene, are then given back to the patient. 

Encouraging results

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 currently within the normal cognitive development range at nine to 18 months post-treatment, but require longer follow-up to assess outcomes. 

After a median of two years, OTL-201 which was generally well tolerated in all the patients, achieved sustained engraftment in the bone marrow. 

Higher amounts of the SGSH enzyme were seen than would be normally found in the blood and cerebrospinal fluid of healthy children. 

Professor Robert Wynn, Chief Investigator on the trial at The Royal Manchester Children’s Hospital, part of Manchester University NHS Foundation Trust (MFT) said: “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.” 

The study was funded by Orchard Therapeutics, sponsored by The University of Manchester and conducted at Manchester University NHS Foundation Trust.

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