Manchester Researchers will tell an international conference today that 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 was funded by Orchard Therapeutics, sponsored by The University of Manchester and conducted at Manchester University NHS Foundation Trust.
It found 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 4-5 years where the most severe stages of disease progression typically present.
The trial patients were 6 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 2 years (range: 9-30 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 1 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 SGSH gene, are then given back to the patient.
This enables patients to then make this missing SGSH enzyme and provide it 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 potentially help stop damage to the brain.
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, 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.”
