• Through the development of ZFP Therapeutics™, ZFP TF™ for therapeutic gene regulation and ZFN™-based therapeutics for therapeutic gene correction and gene disruption.
• Through the use of our technology in enabling technology applications to enhance the production yield of protein pharmaceuticals
  

We are developing engineered Zinc Finger Protein Transcription Factors (ZFP TFs) for Therapeutic Gene Regulation. We couple the ZFP DNA binding domain to a functional domain, creating a ZFP TF™ capable of controlling or regulating a target gene. For instance, an activation domain causes a target gene to be “turned on.” Alternatively, a repression domain causes the gene to be “turned off.”

We are currently developing ZFP TFs for the treatment of the following human diseases:

Diabetic Neuropathy
Diabetic peripheral sensory and motor neuropathy is one of the most frequent complications of diabetes. Apart from rigorous control of blood glucose, the only therapies approved by the FDA for the treatment of diabetic neuropathy are analgesics and antidepressants that address only the symptoms and do not retard or reverse the progression of the disease. Sangamo has ongoing Phase 2 and Phase 1 clinical trials to test a ZFP Therapeutic SB-509, which is designed to up-regulate the endogenous VEGF-A gene. VEGF-A has been demonstrated to have direct neuroproliferative, neuroregenerative and neuroprotective properties.

Sangamo also intends to initiate a Phase 2 repeat-dosing trial in the first half of 2007 in subjects that have a so-called “blocked nerve” or no measurable NCV in their lower limb.

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Cardiovascular Disease and Peripheral Vascular Disease.
There is increasing interest in the development of therapeutic approaches to ischemic heart disease (IHD) and peripheral artery disease (PAD) that might stimulate the human body's natural ability to form new blood vessels, a process called angiogenesis. For this purpose we have developed ZFP TFs designed to activate the expression of angiogenic factors called vascular endothelial growth factors (VEGFs), specifically VEGF A.

We believe that a critical advantage of our ZFP TF technology is the ability to activate the endogenous VEGF A gene resulting in the production of all of the normal splice variants and thus the natural protein isoforms in the ratios normally observed in nature. VEGF A, in its natural state, has multiple splice variants that are involved in the normal physiologic response and appear to be required for the generation of normal, functional vasculature.

In December, 2002 we published initial pre-clinical data in the journal Nature Medicine demonstrating that our ZFP TFs can induce the growth of new blood vessels in rodent models. Our ZFP TFs can stimulate the production of all the major VEGF splice variants in the same proportion normally observed when tissues are oxygen-deprived.

In October, 2004 preclinical animal efficacy studies in the rabbit ischemic hind limb model were published in the American Heart Association Journal Circulation.

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Congestive Heart Failure.
We are developing a ZFP-Therapeutic for the down regulation of Phospholamban, a well-characterized gene target that has a key role in calcium flux in heart muscle and is believed to be directly involved in congestive heart failure.

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Cancer (Glioblastoma)
Gliomas are the most common type of primary brain tumors; 20,000 cases are diagnosed and 14,000 glioma-related deaths occur annually in the United States. Glioblastoma multiforme, a type of glioma, is rapidly progressive and nearly uniformly lethal. In collaboration with researchers at City of Hope who have developed a "zetakine" engineered T-cell therapy for this cancer, Sangamo is developing a ZFP Therapeutic that uses our ZFN technology to disrupt the expression of the gene encoding the glucocorticoid receptor in these T-cells. Sangamo anticipates filing an IND for this therapeutic in 2008.

Cancer Immunotherapy.
Sangamo scientists are engineering replication incompetent adenoviral vectors to deliver ZFP TFs that up-regulate granulocyte macrophage colony stimulating factor (GM-CSF) and pigment epithelial derived factor (PEDF). GM-CSF is a powerful immunostimulator and has been shown to augment anti-tumor immune responses. PEDF is a potent antiangiogenic factor that blocks the angiogenic function of VEGF.   We believe that this approach may be used to treat cancer both at the tumor site and systemically.

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Intractable Neuropathic Pain.
Intractable neuropathic pain is only partially treatable by current medical and non-medical therapies and many small molecule drugs have significant undesirable side effects. We are evaluating the use of ZFP TFs to repress the expression of the specific genes encoding proteins in nerve cell membranes.

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We are engineering ZFNs for Therapeutic Gene Modification:
Gene Correction and Gene Disruption.
The ZFP DNA binding domain may also be coupled to the cleavage domain of a restriction endonuclease—an enzyme that cuts DNA—creating a zinc finger nuclease or ZFN™.

We can design a ZFN to facilitate either :

• ZFN-mediated gene correction: the replacement of a disease-causing mutation with a "normal" or "corrected" DNA sequence,  (e.g. for mongenic diseases such as X-linked SCID, sickle cell anemia, beta-thalassemia) or
• ZFN-mediated gene-disruption: disruption of a disease-related gene resulting in the expression of a truncated or non-functional protein (e.g. for HIV/AIDS treatment)

 Our ZFN technology allows us to facilitate modification of a DNA sequence at a very specific point in the genome without the need for integration of foreign DNA sequences into the genome of cells.  ZFN-mediated gene correction will allow the corrected gene to be expressed in its natural chromosomal context and may provide a safe and effective approach to the precise repair of DNA sequence mutations. In April 2005, in Nature, Sangamo scientists published data demonstrating highly efficient permanent ZFN-mediated gene correction in primary human cells (Urnov, F.D. et al., April 4, 2005, Nature Advance Online Publication doi: 10.1038/nature 03556).