Preliminary results from the first patient treated with Orchard Therapeutic’s OTL-201 show that the investigational gene therapy can increase the levels of sulfamidase — the missing enzyme in Sanfilippo syndrome type A — and normalize those of heparan sulfate.
The therapy also was found to be safe and well-tolerated.
Robert Wynn, chief investigator at the Royal Manchester Children’s Hospital, in the U.K., presented the data in “Ex-Vivo Autologous Stem Cell Gene Therapy Clinical Trial for Mucopolysaccharidosis Type IIIA: Trial in Progress – NCT04201405,” an oral presentation at the 62nd American Society of Hematology (ASH) Annual Meeting, recently held virtually.
“The data presented … represents encouraging progress for patients and families living with MPS-IIIA, a progressive, life-threatening metabolic disease with no approved treatment options,” Wynn said in a press release.
Mutations in the SGSH gene, which contains the instructions to produce the enzyme sulfamidase, underlie the development of Sanfilippo syndrome type A (also known as mucopolysaccharidosis type IIIA, MPSIIIA).
A deficiency in sulfamidase levels leads to a toxic buildup of sugar molecules, including heparan sulfate, inside the brain and other tissues. This buildup eventually results in cell death.
OTL-201 is a cell-based gene therapy that uses a patient’s own blood-forming (hematopoietic) stem cells. Of note, procedures using a patient’s own cells are called autologous, as compared with those using donor cells, known as allogeneic.
Following the harvesting of the patient’s cells, they are genetically modified in the lab to carry a working version of the SGSH gene. A modified, harmless virus is then used as a vehicle to deliver a working copy of the gene into the cells, before they are injected back into the patient.
The open-label, Phase 1/2 study (NCT04201405) is ongoing at the Manchester University NHS Foundation Trust, in the U.K.
The trial’s main goal is to assess the therapy’s efficacy by measuring the levels of sulfamidase in white blood cells, known as leukocytes, after one year. Other goals include overall survival, changes in cognition and behavior, and improvements in the patients’ quality of life. Changes in heparan sulphate concentration levels in the cerebrospinal fluid (CSF), which is the liquid surrounding the brain and spinal cord, and plasma and urine also will be measured.
Participants will be followed for three years after receiving the gene therapy.
Three patients have been successfully enrolled and dosed to date. The trial is looking to recruit up to five patients, ages 3 months to 2 years. More information on how to enroll can be found here.
Preliminary results from the first patient three months after dosing now revealed OTL-201 had a successful engraftment — meaning the cells reached the bone marrow, where they can find optimal conditions to survive and proliferate — as shown by an increase in the levels of blood cells, including neutrophils and platelets.
Sulfamidase levels were increased 150 times above median in leukocytes and 200 times above controls in myeloid lineage cells, those that give rise to different types of blood immune cells.
The therapy also normalized heparan sulfate levels in plasma, CSF, and urine.
The treatment was well-tolerated and no treatment-related side effects (adverse events) or serious adverse events have been reported to date.
Completion of enrollment and the release of interim results are expected to occur by 2021.
“The initial results in the first patient treated provide preliminary evidence of engraftment of cells capable of producing supra-physiological N-sulphoglucosamine sulphohydrolase [sulfamidase] enzyme expression in multiple lineages,” Wynn said.
“We are eager to continue the follow-up of this patient as well as the investigation of OTL-201 in additional patients and look forward to working in close collaboration with Orchard to advance this program with great urgency on behalf of the MPS community,” he added.
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