Blog October 15, 2018

Gene Therapy Update Part 2

Last week we wrote about recent news in the field of CRISPR/Cas9 research. But CRISPR is not the only approach to gene editing under development, nor the most advanced.


First Human Gene Editing Data — But Not from CRISPR


Sangamo Therapeutics, Inc. has been developing an approach to gene editing based on zinc finger DNA-binding proteins (ZFP), engineered to recognize and bind target sequences of DNA. By attaching a nuclease enzyme to the selected ZFP, the resulting Zinc Finger Nuclease (ZFN) can cut DNA at a desired location. ZFNs, targeting different locations on a strand of DNA, can be used to remove or repair a gene fragment. If a cell is treated with ZFNs in the presence of an additional “donor” DNA sequence, a new genetic sequence can be inserted.


mpsSangamo’s work with ZFNs pre-dates CRISPR/Cas9 by several years. The company has conducted human clinical studies with a gene-editing therapeutic candidate, SB-913, for a rare disease called mucopolysaccharidosis (MPS). This condition causes toxic glycosaminoglycans (GAGs) to build up in the cells of an affected patient, producing a range of symptoms that affect multiple organs and shorten the patient’s lifespan. SB-913 is designed to insert the sequence that codes for the enzyme missing in MPS patients.


Sangamo recently presented data from its ongoing Phase 1/2 clinical study in MPS on four of six patients treated with SB-913 in the low and mid-range dose groups. Patients in the study remained on their current MPS enzyme replacement therapy while receiving the gene editing treatment.


The reported results showed that the drug was able to reduce disease biomarkers with an apparent dose-response relationship: patients on the mid-range dose experienced a 51% drop in total urinary GAGs, a 32% drop in dermatan sulfate, and a 61% drop in heparin sulfate after 16 weeks therapy. Patients in the low-dose group experience a slight increase in total GAGs, with a slight rise in dermatan sulfate offset by a 23% decline in heparin sulfate. The researchers said they had not expected to see an impact on urinary GAG in this timeframe, and so were encouraged by the early results. Industry analysts were less impressed, as they were hoping to see clear evidence of an increase in plasma ironate-2-sulfatase (IDS), an enzyme believed to be necessary for GAG reduction.


No safety issues have been reported with SB-913 treatment to date. Sangamo is now preparing to initiate another trial at higher doses, and is evaluating the possibility of removing treated patients from their enzyme replacement therapy.


Amicus Signs $100M Gene Therapy Deal


Rare disease company Amicus Therapeutics is acquiring Celenex’s portfolio of 10 gene therapies for rare diseases for $100 million and the promise of up to another $350 million in regulatory and sales milestones. Interestingly, Amicus and Celenex share similar stories, in that each was founded by a parent dealing with a child with a rare genetic disease.


The Gray family: Gordon, Charlotte, Kristen, and Gwenyth
The Gray family: Gordon, Charlotte, Kristen, and Gwenyth

The 10 gene therapy programs were all developed by researchers at Ohio State University and The Center for Gene Therapy at the Research Institute at Nationwide Children’s Hospital, which also developed the gene therapy for spinal muscular atrophy that Novartis bought from AveXis for $8.7 billion. The lead programs are potentially curative treatments for CLN6, CLN3 (both in early stage clinical testing) and CLN8 Batten’s disease, the degenerative neurological condition affecting the two daughters of Celenex’s founder, Gordon Gray.


The program targeting the CLN6 gene has already generated a small amount of early human data from two siblings treated for two years with the gene therapy: the younger one’s motor and language function have not worsened since the start of therapy, and disease progression in the older child has stabilized. Included in the remaining seven programs are potential treatments for Neimann-Pick disease type c, Wolman disease, and Tay-Sachs disease, all in preclinical development.


A Milestone in Gene Therapy Oversight


In a noteworthy milestone in the history of gene therapy, the U.S. National Institutes of Health and the Food and Drug Administration have called for eliminating the involvement of the Recombinant DNA Advisory Committee (RAC) in overseeing human gene therapy experiments.


The RAC was originally created in 1974 to set guidelines for recombinant DNA (rDNA) research given early concerns about potential risks of that technology. Composed of basic scientists, physicians, ethicists, theologians and patient advocates, the RAC played a major role in overseeing early research and influencing regulatory policy over the development of rDNA as it pertains to safety. In 1991, RAC’s role was expanded to encompass the review and approval of human gene therapy research, with a focus on biosafety.


The new recommendations to end the RAC’s involvement in gene therapy trial oversight hand those responsibilities to the local Institutional Review Boards, who typically review all clinical trials at their institutions for safety risks and other factors. This recommendation marks the end of an era and the maturing of U.S. science’s familiarity and comfort with gene therapy.