Diabetic peripheral sensory motor neuropathy is one of the most frequent complications of diabetes and affects an estimated 50 per cent of diabetics who have lived with their diabetes for ten years or more. Symptoms include numbness, tingling sensations and pain particularly in the toes or feet. This is gradually replaced by loss of sensation and motor function as nerve damage progresses.
The phase I clinical trial is expected to commence after the US Food and Drug Administration (FDA) cleared an Investigational New Drug (IND) filing for the single blind, placebo-controlled, dose-escalation trial in February 2005.
The trial is expected to treat approximately 12 patients in the trial and subjects will receive injections that target the major peripheral nerves in the legs and feet. The first dose level will be injected in a distribution to treat nerves in the foot, the second will be distributed to include nerves in the outside of the lower leg and foot, the third for the whole lower leg and foot and the fourth for the major nerves in the whole leg from the thigh down.
The trial is expected to take approximately 12 months to screen and enroll patients and 6 months for patient follow-up.
The novel therapy, SB-509, is an injectable formulation of plasmid DNA that encodes a zinc finger DNA-binding protein transcription factor (ZFP TFTM), designed to upregulate the vascular endothelial growth factor A (VEGF-A) gene. VEGF-A has been demonstrated to have direct neurotrophic and neuroprotective properties. In preclinical animal efficacy studies in a diabetic rat model, SB-509 has proven effective in protecting motor and sensory nerve function from disease-induced nerve damage.
"In previous studies, VEGF-A has been shown to be efficacious for maintenance of nerve function in this condition and we believe that our approach of activating the patient's own VEGF-A gene directly may have important advantages over introducing a cloned gene or recombinant protein," said Dale Ando, Sangamo's vice-president of therapeutic development and chief medical officer.
Sangamo has engineered a class of DNA-binding proteins known as zinc finger DNA-binding proteins (ZFPs). By engineering ZFPs that recognise a specific DNA sequence Sangamo has created ZFP transcription factors (ZFP TFTM) that can control gene expression and, consequently, cell function.
Sangamo is also developing sequence-specific ZFP Nucleases (ZFNs) for therapeutic gene modification as a treatment and possible cure for a variety of monogenic diseases such as sickle cell anaemia and for infectious diseases such as HIV.
"We are successfully translating our zinc finger DNA-binding protein (ZFP) technology into products that are now being tested in human clinical trials to address significant unmet medical needs," said Edward Lanphier, Sangamo's president and CEO.
The American Diabetes Association estimates that there are currently approximately 18.3 million people with diabetes in the United States. According to the CDC, diabetes is becoming more common in the United States. From 1980 through 2002, the number of Americans with diabetes more than doubled.
Despite adequate treatment, these areas of trauma frequently become infected and this infection may spread to the bone, necessitating amputation of the leg or foot. More than 60 per cent of non-traumatic lower-limb amputations in the United States occur among people with diabetes. In the period from 2000 to 2001 this translated to approximately 82,000 amputations.