Stem Cell Gene Therapy Improves Signs of Sanfilippo A: Trial Data

Phase 1/2 clinical trial shows treatment generated high levels of SGSH

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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Stem cell gene therapy in children with Sanfilippo syndrome type A was well-tolerated and generated high levels of SGSH, the enzyme missing in people with the condition, according to a Phase 1/2 clinical trial.

Elevated SGSH enzyme activity resulted in a rapid and significant drop in urinary and blood levels of heparan sulfate, the complex sugar that builds to toxic levels without the enzyme.

Although cognitive assessments are ongoing, early data suggested improvements with long-term follow-up compared to the natural history of Sanfilippo A.

The study abstract, “Biochemical Engraftment and Clinical Outcomes Following Ex-Vivo Autologous Stem Cell Gene Therapy for Mucopolysaccharidosis Type IIIA,” was published in the journal Blood. Data will be presented at the American Society of Hematology (ASH) Annual Meeting and Exposition, held Dec. 10–13.

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Autologous ex vivo hematopoietic stem cell gene therapy

In Sanfilippo type A, also called mucopolysaccharidosis type IIIA, defects in the SGSH gene lead to a faulty SGSH enzyme that is unable to break down heparan sulfate. As a result, the sugar builds up to toxic levels in cells, causing tissue damage, especially in the brain.

Autologous ex vivo hematopoietic stem cell gene therapy (HSC-GT) is an investigational treatment for Sanfilippo type A. It is designed to deliver a functional copy of the SGSH gene into a patient’s own hematopoietic stem cells, which are stem cells that give rise to all blood cells. Modified cells are then returned to the patient in the form of a stem cell transplant to allow the production of the missing SGSH enzyme.

Preclinical studies in a mouse model of Sanfilippo A by researchers in the U.K. demonstrated HSC-GT led to the detection of SGSH enzyme six months after transplant. As a result, heparan sulfate levels and mouse behavior normalized.

Stable engraftment was then demonstrated with human HSC cells transplanted into mice, “supporting the translation of this work to the clinic,” the team noted.

5 patients treated in clinical trial, 1 treated off-trial

The Phase 1/2 clinical trial (NCT04201405), sponsored by the University of Manchester, has treated five patients with severe Sanfilippo A, ages 6 months to 2 years. An additional child was treated off-trial, at 2.5 years, on a compassionate-use basis.

All children underwent stem cell collection, followed by modification with the functional SGSH gene. Patients received myeloablative busulfan conditioning immediately before transplant, a regimen that helps remove the patient’s diseased cells before HSC infusion.

Up to study submission, three participants had more than 18 months of follow-up post-transplant, one had more than one year, and another had more than nine months of follow-up. The off-trial patient treated at 2.5 years had more than three years of follow-up.

Primary goals include safety and tolerability as well as SGSH enzyme activity in white blood cells one year after transplant. Secondary outcomes assess cognition using Bayley scales of infant and toddler development. Participants will be followed for a minimum of three years.

Engraftment of transplanted cells was rapid. The median time for red blood cell engraftment was 25 days, for platelets 28 days, and 19 days for neutrophils, a type of white blood cell. Engraftment has been sustained to date in all patients.

At one month, SGSH enzyme levels in white blood cells were 38–91 times higher than the median normal range, referred to as supra-physiological levels. Excess SGSH also was rapidly detected in blood, bone marrow, and cells with CD15 protein, a marker found on some immune cells.

By six months, normal or above normal levels of SGSH enzyme were found in patients’ cerebrospinal fluid (CSF), the colorless liquid surrounding the brain and spinal cord. Treatment rapidly reduced excess heparan sulfate levels by more than 90% in urine samples and 82% in blood.

Data from the child treated off-trial assessed at three years post-transplant continued to show high levels of SGSH enzyme and cognitive outcomes indicating improvement compared to the natural history of untreated Sanfilippo A patients.

Cognitive assessments of trial participants are ongoing. Early outcomes suggest a change to neurological characteristics of Sanfilippo A in one patient, while three patients are currently within the normal developmental quotient range and require longer follow-ups.

All children in the trial also showed earlier SGSH production in white blood cells and other lineages compared to the off-trial patient treated at an older age.

“Treatment with ex vivo autologous HSC-GT is generally well tolerated and delivers supra-physiological levels of enzyme throughout the body,” the researchers concluded.