First Results of In Vivo Gene Editing Trial of MPS II Treatment Show Only Small Benefit

Sangamo Therapeutics reported preliminary results of its gene-editing product candidate SB-913 that showed limited benefit as a treatment for MPS II, a rare lysosomal storage disorder.

In the first trial in humans of a gene-editing technology, Sangamo’s zinc finger nuclease (ZFN) technology did what it was supposed to do—edit the mutated gene that causes the disease—but did not lead to a sustained therapeutic effect for the patients in the study.

Mucopolysaccharidosis type II, also known as MPS II or Hunter syndrome, is caused by a deficiency of iduronate-2-sulfatase (IDS), a lysosomal enzyme that is required to break down or recycle the toxic buildup of glycosaminoglycans (GAGs). Without IDS enzyme activity, GAGs accumulate in cells throughout the body, leading to widespread tissue and organ damage. The current standard-of-care treatment for MPS II is enzyme replacement therapy, given weekly as intravenous infusions.

Sangamo’s interim data, presented at a conference in Florida, came from the early-stage CHAMPIONS trial in eight patients who were withdrawn from enzyme replacement therapy and dosed at three levels of the experimental gene therapy. SB-913 is designed to insert a normal copy of the IDS gene into a precise location in the DNA of liver cells with the goal of enabling a patient’s liver to produce a continuous supply of functional IDS enzyme.

In the study, patients were separated into three dosing groups. In the low dose group, there was no evidence in gene integration in one patient, while the second patient was not evaluable. Two patients in the middle dose group showed evidence of gene integration but did not did not show evidence of increased IDS enzyme production. Of the two patients evaluated in the high dose group, one was not evaluable while the other showed increased IDS enzyme production that was not sustained due to signals of liver toxicity. Sangamo is hoping that liver biopsies on the high dose cohort, which will be available later this year, will show complete integration of the working gene and improve its therapeutic effect.

“The interim results provide preliminary evidence that in vivo genome editing occurred and that genome-edited liver cells are able to generate active IDS enzyme in patients with MPS II,” said Joseph Muenzer, a professor of pediatrics and genetics at the University of North Carolina School of Medicine in Chapel Hill and a lead study investigator. “More data are needed to understand whether the small increases in IDS enzyme activity observed can translate into improved outcomes in MPS II patients treated with this first generation of SB-913. I look forward to reviewing additional data later this year from the five patients who have received the high-dose of SB-913.”

Sangamo also presented early results on SB-318 in the treatment of MPS 1, or Hurler syndrome, that showed increased enzyme activity. 

“The SB-913 and SB-318 data presented today represent an encouraging first step in the translation of genome editing technology from basic research to genomic medicine. Further data will be available throughout 2019 and will help inform our understanding of these early results,” said Sandy Macrae, CEO of Sangamo.

Sangamo has developed second-generation, potentially more potent ZFN constructs designed to increase editing efficiency. These second-generation ZFNs are expected to be available for evaluation in the clinic later this year.

Photo: Sandy Macrae, CEO of Sangamo

Author: Rare Daily Staff