Madrid: Clinical Trials Update—Where Do Things Stand?
Nerve growth factor gene therapy, diabetes drugs, a pooled antibody stew, hormones, and radical scavengers—it’s not like all researchers are focusing squarely on immunotherapy or secretase inhibitors in their search for better Alzheimer drugs. Last July at the 10th International Conference on Alzheimer’s Disease and Related Disorders in Madrid, several dozen groups presented data on human tests—ranging from tiny pilots to large controlled cohorts—of a panoply of approaches. None produced spectacular “light-bulb” effects, but some bear watching. The news moment of ICAD has passed as researchers are already beginning to look toward the Society for Neuroscience meeting next month in Atlanta, Georgia. But since trial data appear in the formal literature with long delays, if at all, here is one more ICAD roundup of selected trial presentations. As always, we invite additions and corrections. If this writer missed a presentation on “your” trial, we’ll gladly add your comments.
Nerve Growth Factor Gene Therapy
Mark Tuszynski, at the University of California, San Diego, explores the potential of delivering nerve growth factor specifically to cholinergic neurons of the forebrain’s nucleus basalis to protect neurons against degeneration in Alzheimer disease. Tuszynski has for years persisted against skeptics who maintain that his method of choice—gene therapy in the brain—is not ready for prime time, too dangerous, too expensive, and too high-tech. All of that might be so, except the approach looks like it might just work. That, at least, is where things stand currently.
Tuszynski noted that prior work on models ranging from aging to injury, excitotoxicity, and amyloid overexpression all substantiate the rationale of using nerve growth factor in an effort to stem neuronal death and support repair. The leap to success in humans, Tuszynski believes, hinges on delivering this potent agent to its designated area but nowhere else. Last year, Alzforum covered formal publication of phase 1 results, to 22 months of follow-up. In Madrid, Tuszynski added data for up to five years after the beginning of this trial.
This far out, the procedure appears safe when administered under anesthesia, causing no pain or weight loss. As is typical during neurosurgical procedures, the patients initially were awake during the surgery; however, having AD, some forgot to stay still and moved, causing one person’s death 5 weeks later from deep vein thrombosis following a brain hemorrhage. The person’s autopsy results suggested robust NGF expression and cholinergic axons sprouting into the graft area. “There was a classic trophic response to NGF, so AD neurons can respond to this growth factor in the aged brain,” Tuszynski said. Subsequent surgeries were done under anesthesia, without complication.
The long-term data showed that the patients who received bilateral injections of NGF-releasing cells maintained stable cognitive performance in MMSE and ADAS-Cog, as well as their ability to live independently. Patients who received injections into only one side of their brain declined on these scores. While Tuszynski considers these data encouraging, he noted that the absence of controls and the small number of patients preclude stronger conclusions. At this stage, Ceregene, a California biotech company he co-founded, has filed an investigational new drug (IND) application with the FDA for a phase 1/2 trial. Pending approval, it will test a new gene delivery method using adeno-associated virus (AAV), not the older method of using a patient’s own, individually engineered fibroblasts. The AAV method hopefully will prove to be simpler and ensure sustained gene expression over time, Tuszynski noted. In addition, six patients have been enrolled in a phase 1 trial overseen by David Bennett at Rush University Medical Center in Chicago, and Ceregene is planning a 50-patient phase 2 trial with sham surgery controls, Tuszynski said.—Gabrielle Strobel.
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