Sangamo and CHDI Foundation Ally on ZFP Huntington Disease Therapeutic

Sangamo BioSciences and the CHDI Foundation are teaming up to develop a disease-modifying therapeutic for Huntington disease (HD) based on Sangamo’s zing finger DNA-binding protein (ZFP) technology. The aim is to develop a ZFP transcription factor (ZFP TF) capable of altering expression of the mutated huntingtin gene and so directly impact on disease progression. CHDI says it believes the ZFP platform could be harnessed to modify various aspects of HD pathology.

“The causative genetic defect in HD provides a validated target for intervention using a ZFP-based approach,” remarks Philip Gregory, D.Phil., Sangamo’s CSO and vp for research. “Our collaboration will initially focus on developing ZFP therapeutics to lower levels of the mutant huntingtin protein in mouse and human cells.

Sangamo is a clinical-stage biopharma developing ZFP candidates for the regulation of gene expression and gene modification. The firm claims linking ZFPs to functional domains that normally activate or repress gene expression enables the generation of ZFP TFs capable of turning genes on or off. ZFPs can also be attached to nuclease domains to create zinc finger nucleases (ZFNs) capable of effecting precise gene editing in cells.

The firm has three zinc finger-based drugs in clinical development. Lead candidate SB-509 is a ZFP TF, designed to up-regulate the gene for vascular endothelial growth factor-A (VEGF-A). In development for the treatment of neurodegenerative diseases, SB-509 is currently undergoing a Phase IIb trial in subjects with moderately severe diabetic nephropathy. Evaluation of the candidate is also ongoing for indications including ALS, spinal cord and traumatic brain injury, and stroke.

SB-728 is a ZFN-based approach to modifying the CCR5 co-receptor expressed on CD4+ T cells and so prevent HIV infection. The aim is to use the ZFN-mediated gene-editing technology to replicate a naturally occurring human mutation that renders individuals largely resistant to infection with the most common strain of HIV. Lead candidate SB-728-T is an autologous modified T cell product being evaluated in one Phase I/II and two Phase I clinical trials to in patients with HIV-1. A preclinical-stage program is also in progress to develop an SB-728 hematopoietic stem-cell product.

Sangamo’s third clinical candidate, SB-313, is an off-the-shelf ZFN-based glucocorticoid-resistant cytotoxic T-cell product in development for glioblastoma therapy. The result of a collaboration with City of Hope clinicians, the Phase I-stage product comprises T cells that are resistant to glucocorticoid therapy as a result of ZFN engineering, and which also express an engineered protein known as an IL-13 zetakine that targets killer T cells to glioblastoma cells in the brain.