Malorye Allison Branca Contributing Editor
While Many Companies Are Jumping on the CRISPR Gene-Editing Train, Sangamo Presses Ahead with Its Use of Zinc Finger Proteins for Its Gene-Editing Program
The first ever in vivo genome editing trials are currently recruiting. Sangamo, which is sponsoring the trials, already has an anti-HIV gene-editing based product in trials, but that involves removing stem cells, editing them, and then returning them to the patient (i.e. ex vivo treatment). That treatment knocks out the CCR5 gene, thereby protecting cells against HIV infection.
“Until now, gene editing has mostly focused on ex vivo approaches,” said Michael Holmes, Sangamo’s vice president of research. “We are now introducing nucleases into the body.” Sangaomo’s approach uses zinc finger DNA-binding proteins (ZFPs) consist of a tandem array of zinc fingers, which are short peptides of 28 residues that recognize three-to-four base pairs. With an attached nuclease, a zinc finger protein can cut DNA, and either delete and/or add specific sequences.
The company was founded in 1995 and launched its first HIV trials in 2009. But this year could be a major turning point for Sangamo’s gene-editing program.
One company-sponsored study will introduce a gene into the livers of hemophilia B patients. Since the liver normally generates the clotting factor these patients need, the hope is that inserting the corrected gene will help prevent uncontrolled bleeding episodes.
Sangamo is also trying this approach against Hurler and Hunter syndromes. Hurler syndrome is also known as mucopolysaccharidosis type I (MPS I) and is caused by an alpha-L iduronidase deficiency. Hunter syndrome, meanwhile, is also called mucopolysaccharidosis II (MPS II), and is a lysosomal storage disease caused by iduronate-2-sulfatase (I2S) deficiency.
“What the field of gene editing has been doing—and Sangamo, in particular—is pushing the sensitivity of the assays used to assess off-target effects,” explained Edward Rebar, vice predident of technology at Sangamo. Several such assays are available and widely used, including GUIDE-Seq and CIRCLE-Seq. “As more therapies push toward the clinic, optimizing these become a priority,” he added. In addition, the company has placed spginficant focus on improving the efficiencies of the nucleases they use, and optimizing delivery. Sangamo uses adeno-associated virus (AAV)6 vectors. They are also investigating lipid nanoparticulars, mRNA, and other forms of AAV.
Naturally, Sangamo is also being strategic about which indications they tackle first. It started with the ex vivo approaches, editing genes in T cells and stem cells. As the company moves to in vivo gene editing, delivery will become a major focus. “Delivery is the challenge, but as we address that we will be able to reach more and more cell types,”
This article was originally published in the September/October 2017 issue of Clinical OMICs. For more content like this and details on how to get a free subscription to this digital publication, go to www.clinicalomics.com.