Diabetic Neuropathy (DN) (SB-509)
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's drug, SB-509, is designed to up-regulate the endogenous VEGF-A gene. VEGF-A has been demonstrated to have direct neuroproliferative, neuroregenerative and neuroprotective properties.

We have completed a placebo-controlled Phase 1 clinical trial (SB-509-401) in subjects with mild to moderate DN. The data from this trial were very encouraging demonstrating that the drug was well-tolerated and that there were clinically relevant improvements in a number of measures of nerve health in SB-509 treated subjects compared to placebo-treated subjects.

We have an ongoing Phase 2b clinical trial (SB-509-901), and two completed Phase 2 trials (SB-509-601 and SB-509-701) with this drug in this indication:

SB-509-901: A repeat-dosing, placebo-controlled, double-blind multicenter trial in subjects with moderately severe diabetic neuropathy is designed to finalize dose, schedule and primary and secondary endpoints for pivotal Phase 3 trials. The trial will accumulate data on approvable endpoints including Neurological Impairment Score in the Lower Limb (NIS-LL), nerve conduction velocity in the sural nerve (sNCV), as well as quality of life assessments (QOL) and intraepidermal nerve fiber density (IENFD).

SB-509-601: A repeat-dosing, placebo-controlled, double-blind multicenter trial in subjects with mild to moderate diabetic neuropathy to evaluate the safety of SB-509 administration in this population. This trial is complete. Interim data at 180 days post treatment demonstrated that the drug was safe but that no difference was observed in a number of measures of nerve health between placebo and SB-509-treated subjects. Further analysis of these data demonstrated a direct neuroregenerative effect of SB-509 treatment that resulted in a statistically significant (p value = 0.02) increase inintraepidermal nerve fiber density (IENFD) in subjects with DN. IENFD is a validated, direct histologic measurement of small unmyelinated sensory nerve fibers in the skin, the primary sensory nerves involved in DN and haas been correlated with correlates with neuropathy severity in diabetes, nerve fiber densities derived from sural nerve biopsies and levels of vascular endothelial growth factor-A (VEGF-A). In subjectsin this trial with more severe neuropathy, as judged by their baseline IENFD, a greater nerve regrowth response to SB-509 treatment was observed compared to regrowth responses in placebo-treated subjects. In addition, subgroup analyses using baseline severity of disease for both neurologic and vascular disease as a selection criterion demonstrated that SB-509 treatment resulted in correlative, clinically-relevant improvements in NIS-LL and sNCV in subjects with moderate to severe disease. These data informed the design of our Phase 2b trial SB-509-901.

SB-509-701: Single-blind, repeat-dosing trials of SB-509 in subjects that have severe diabetic neuropathy characterized by at least one nerve in their lower limb for which no measurable NCV can be measured. This trial is designed to evaluate safety of SB-509, dosing frequency and effect of the drug on sural nerve NCV. Data are expected from this trial in the first half of 2010.

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Amyotrophic Lateral Sclerosis (ALS) (SB-509)
We are also evaluating SB-509 in amyotrophic lateral sclerosis (ALS). ALS, commonly referred to as “Lou Gehrig’s disease,” is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord and is generally fatal. The progressive degeneration of the motor neurons in ALS is the primary reason that the disease is fatal. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. Muscle weakness is a hallmark initial sign in ALS, occurring in approximately 60% of patients. The hands and feet may be affected first, causing difficulty in lifting, walking or using the hands. As the weakening and paralysis continue to spread to the muscles of the trunk, the disease eventually affects speech, swallowing, chewing and breathing. When the breathing muscles become affected, ultimately, patients need permanent ventilatory support in order to survive. More than 5,600 Americans are diagnosed with ALS each year. Approximately 35,000 people at any given time are living with ALS in the United States. There are no drugs available to cure ALS. The FDA has approved a single medication, Rilutek© (Riluzole) which modestly increases lifespan in ALS patients.

There are both animal and clinical data that suggest that a defect or deficiency in VEGF expression plays a role in ALS. In an ongoing Phase 2 trial (SB-509-801), we are evaluating whether a regional muscle or systemic effect of SB-509 delivery will result in a therapeutic effect in ALS. Preliminary data presented in december 2009 at the 20th International Symposium on ALS/MND demonstrated an approximate doubling of frequency of improved muscle function in subjects with ALS who received two treatments of SB-509 (32%) compared to matched historic controls (17%). The trial is fully accrued and data are expected in the second half of 2010.

Pre-clinical Programs.
We have ongoing preclinical programs to evaluate ZFP TFs for nerve regeneration in conditions such as spinal cord injury, neuropathic pain and Parkinson's Disease.
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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-disruption: disruption of a disease-related or undesirable gene resulting in the expression of a truncated or non-functional protein (e.g. for HIV/AIDS treatment) or
• 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)

 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 the journal 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).

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We are developing ZFNs for therapeutic gene disruption as a potential therapy for:

Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS)
HIV infection results in the death of immune system cells and thus leads to AIDS, a condition in which the body’s immune system is depleted to such a degree that the patient is unable to fight off common infections and ultimately  succumbs to opportunistic infections or cancers.  CCR5 is the co-receptor for HIV entry into T-cells and without CCR5 expressed on their surface, HIV cannot infect these cells.  A population of individuals has been identified that is immune to HIV infection, despite multiple exposures to the virus. They have a natural mutation, CCRΔ532, that results in the expression of a shortened, non-functional CCR5 protein. This mutation appears to have no observable deleterious effect on the growth or survival of these individuals. We are using our ZFN-mediated gene disruption technology to disrupt the CCR5 gene in cells of a patient’s immune system to make these cells permanently resistant to HIV infection.  The aim is to provide a population of HIV-resistant cells that can fight opportunistic infections. In collaboration with scientists at the University of Pennsylvania and the University of Los Angeles California, UCLA, we are pursuing both ex- and in vivo approaches in T-cells and hematopoietic stem cells. In June 2008, we published the positive preclincal data from this program generated in a mouse model of HIV infection (Nat Biotechnol. 2008 Jul;26(7):808-16). In 2009, Sangamo initiated two Phase 1 clinical trials to evaluate our ZFP Therapeutic SB-728-T in T-cells for the treatment of HIV/AIDS.

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Cancer (Glioblastoma multiforme)
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 filed an IND for this therapeutic in 2009 and in 2010 announced the initiation of a Phase 1 clinical trial that will be conducted by its collaborators at City of Hope.

We are also developing ZFNs for therapeutic gene correction of monogenic diseases such as:

X-linked Severe Combined Immunodeficiency (X-linked SCID)
Mutations in the gene encoding the IL2Rγ protein invariably cause X-linked SCID (X-linked Severe Combined Immunodeficiency Disease) or so-called Bubble–boy disease. Patients with such mutations do not produce a functional IL2Rγ protein; never develop a functional immune system and die of severe infections within 12-18 months of birth. Sangamo scientists have used ZFN-mediated gene correction in model cells and primary cells to correct this genetic lesion.  This research stage work was published in Nature magazine in April, 2005.  With our collaborators we are developing these ZFNs for use in hematopoietic stem cells as a potential therapeutic.

Hemoglobinopathies
Mutations in the gene encoding the globin gene cause a variety of inherited conditions of the blood such as sickle cell disease and beta-thalassemia. Sangamo scientists have used ZFN-mediated gene correction in primary cells as an approach to correct such genetic lesions.   With our collaborators we are developing these ZFNs for use in hematopoietic stem cells as potential therapeutics.

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Commercialization of ZFP Therapeutics
We plan to develop and commercialize ZFP Therapeutics in partnership with pharmaceutical and biotechnology companies. For certain ZFP Therapeutics we intend to negotiate partnerships with terms that will provide partners with exclusive rights to the regulation of specific genes for certain clinical indications and geographic areas covered under the agreement. For other ZFP Therapeutics, we intend to retain certain commercial product rights or negotiate partnerships for such products after substantial internal development.

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