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"The data obtained in this clinical trial are very interesting and mayhave important implications for assessing biological activity and efficacy ofthis therapeutic strategy," commented the presenter, Robert Mitchell, M.D., ofthe department of medicine at Duke University Medical Center. "Several of thesubjects in this trial were already scheduled for amputation but chose toenroll in this important trial. Within a subgroup analysis, the datademonstrate that the best clinical responders had the largest fold increase inbone marrow stem cells twelve days after dosing. Increased mobilization ofstem cells, which may be involved in tissue regeneration and repair, mayprovide an early indication of a biological response to this therapy."
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"These data, and other clinical and preclinical observations of naturalmobilization of stem cells in a response to our ZFP activator of VEGF, arevery interesting and form the basis of our most recently initiated Phase 2study (SB-509-703)," commented Dale Ando, M.D. Sangamo's vice president oftherapeutic development and CMO. "In this Phase 2 clinical trial we aremonitoring changes in the numbers of stem cells in the circulation of subjectswith mild to moderate diabetic neuropathy after treatment with our ZFPTherapeutic. We believe that the study may provide us with valuablepharmacodynamic data on the relationship between stem cell mobilization andtreatment."
Clinical Results Presented at the ISCT Meeting
The data presented at the ISCT meeting on Sunday, May 18, 2008, werecollected from a single arm, open-label, Phase 1 clinical trial in subjects(n=20) with critical limb ischemia (Rutherford Grade 4/5). Qualifyingsubjects were assigned to receive dose-escalating, intra-muscular injectionsof ZFP-VEGF in the ischemic leg (index leg). Subjects were clinicallyclassified as significant responders, minimal responders or non-respondersbased on their tissue oximetry readings. Circulating progenitor cells weremeasured and quantitated by FACS analysis based on aldehyde dehydrogenaseactivity (ALDH+) and expression of CD34 in 11 subjects. These measures weresubsequently compared with clinical outcomes. Additionally, bone marrowsamples from 8 patients were evaluated for ALDH+ cells on Day 0 and Day 12post treatment to determine the effects of ZFP-VEGF on progenitor cellmobilization.
Clinicians observed a mean increase in circulating CD34+/ ALDH + cells of1.3 fold from Day 0 to Day 30 post-treatment and 1.9 fold from Day 0 to Day 90post-treatment. In addition, subjects with 7 to 9 fold increases in bonemarrow stem cells were also the best clinical responders as assessed byincreased tissue oxygen perfusion, improved pain scores, ulcer healing andamputation rates.
Aldehyde bright stem cells can be identified in the subject's blood orbone marrow by staining with a substrate of aldehyde dehydrogenase, an enzymethat is highly expressed in stem cells. Stem cells can self-renew through celldivision
