Researchers will tell an international conference today that a new gene therapy for Sanfilippo disease – also known as childhood dementia – has shown promising early results in a proof-of-concept study.
Developed by Manchester University NHS Foundation Trust, Orchard Therapeutics and The University of Manchester, four out of five patients in the study have gained cognitive skills in line with development in healthy children after being given the investigational drug OTL-201.
Some children had normal speech acquisition and were able to carry out complex play requiring concentration, which is typically not seen in children with Sanfilippo.
However, the researchers urge caution as the majority of patients have not reached the age 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 MPS-IIIA- is a genetic disease with devastating effects on the central nervous system affecting around one in 70,000 children.
The children lack an enzyme which breaks down large sugar molecules. As the molecules accumulate in the cells of the body, they cause irreparable damage to all organs including the brain, causing widespread inflammation and a loss of sensitive brain tissue.
The treatment works by replacing the missing SGSH gene in the patient’s own blood stem cells using a modified virus, known as a lentiviral gene therapy vector. The patient’s blood stem cells, now including the SGSH gene, are then transplanted back into the patient via the drug OTL-201.
This provides the missing SGSH enzyme throughout the body from blood cells made in the bone marrow. These stem cells can make monocytes, which are specialised blood cells able to enter the brain. This means they can release SGSH enzyme to help stop damage to the brain.
The results showed:
A marked improvement 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 development quotient range at nine to 18 months post-treatment, but require longer follow-up to assess outcomes.
After a median two years, the drug which was 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 body.
Six serious adverse events have been reported in patients in the study, but with no long-term effects. None were thought to be caused by the drug itself.
Professor Brian Bigger, who carried out the preclinical work said: “We have been hopeful this therapy will be transformative for patients – and these early results are very positive – but there’s still a long way to go.
“Importantly, the safety of the therapy is looking very good in these patients so far, with the lentiviral vector integrating into multiple blood stem cells that go on to make the blood system and the missing enzyme in patients.
“The human monocyte-specific promoter that we included in the lentiviral vector seems to have a very low risk of causing insertional mutagenesis – the accidental switching on of genes causing cancer- for these patients to date. This is critical for the future application of this therapy.”
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.”
Professor Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at the Manchester Centre for Genomic Medicine at Saint Mary’s Hospital and Clinical Director of NIHR Manchester Clinical Research Facility at Royal Manchester Children’s Hospital, said: “There are currently no other treatment options for children with MPSIIIA. We hope this therapy will have a positive impact on the lives of our children and their families, improving the symptoms of this devastating disease.”
Dr Leslie Meltzer, Chief Medical Officer, Orchard Therapeutics said: “These promising findings continue to demonstrate the ability of our HSC gene therapy platform to enable the migration of gene-corrected cells into the central nervous system and the localized delivery of therapeutic enzymes and proteins to the brain to potentially correct neurodegeneration in multiple severe conditions, building on our programs in metachromatic leukodystrophy and MPS-IH.
“While these early results are encouraging, longer follow up is needed, as the majority of the patients in this trial have not reached the age where the most severe stages of disease progression typically manifest. We are working with our collaborators at The University of Manchester and Royal Manchester Children’s Hospital to continue following patients in this ongoing study and more fully characterize the clinical profile of OTL-201.”