Results from the first gene therapy trial for patients with Alzheimer’s disease have shown that the procedure appeared to significantly slow progression of the degenerative disorder, with one patient even experiencing new brain tissue growth, according to Mark Tuszynski, MD, PhD. Although the research is preliminary, Dr. Tuszynski hopes that gene delivery of nerve growth factor may be able to significantly reduce cognitive decline in patients with Alzheimer’s disease for as long as three to four years, thereby improving their quality of life and delaying entry to a nursing home. Patients with early or moderate Alzheimer’s disease are the most likely candidates to respond favorably to the procedure, given the neuroprotective features of nerve growth factor.

The phase I clinical trial yielded three key findings. “We found the first evidence in the human brain that degenerating neurons can mount a trophic—or growth—response to therapeutically administered growth factors,” Dr. Tuszynski told Neurology Reviews. “Second, we found a significant increase in cortical metabolism after nerve growth factor delivery to patients with Alzheimer’s disease, a reversal of the decrement normally observed over time. Third, and these findings must be interpreted cautiously due to the small sample size and absence of placebo controls, we found a reduction of 36% to 51% in the rate of cognitive decline in our patient cohort for a period of about two years. If future larger, controlled, and blinded trials confirm this observation, then nerve growth factor gene delivery would substantially exceed the efficacy of current therapies for Alzheimer’s disease.” Dr. Tuszynski is a Professor of Neurosciences and Director of the Center for Neural Repair at the University of California, San Diego, and a neurologist at the VA Hospital in La Jolla.

GENE DELIVERY AND NERVE GROWTH FACTOR

Dr. Tuszynski and colleagues administered ex vivo nerve growth factor gene delivery in eight individuals with mild Alzheimer’s disease by implanting autologous fibroblasts genetically modified to express human nerve growth factor into the forebrain, as reported in the April 24 online edition of Nature Medicine. Mean age of participants (five females) was 67, with a range of 54 to 76 years. The first two subjects received injections in the right brain only; the remaining six received bilateral injections. Cognitive outcomes were measured at regular intervals, and serial PET scans were obtained six to eight months apart in four bilaterally treated subjects using 18-fluorodeoxyglucose imaging. Two subjects underwent preoperative and six-month postoperative scans, and two had two serial postoperative scans at 10 and 18 months after delivery of nerve growth factor.

Stereotaxic injections were completed safely in six of eight subjects. After following up those six patients for a mean of 22 months, the researchers observed no long-term adverse effects from the nerve growth factor. An evaluation of the Mini-Mental State Examination and the Alzheimer’s Disease Assessment Scale–cognitive subcomponent suggested that the rate of cognitive decline had improved. In addition, serial PET scans showed significant increases in cortical 18-fluorodeoxyglucose after treatment.

“In the six- to 18-month period after nerve growth factor delivery, corresponding to the predicted period of active growth factor enhancement of cholinergic cortical projections, cognition apparently improved or stabilized in five of six subjects,” stated Dr. Tuszynski. “By comparison, currently approved medications for Alzheimer’s disease have an estimated impact on these cognitive measures of 5% and are not known to affect decline over prolonged periods.”

The first two participants who underwent the procedure were sedated but not anesthetized and moved while cells were being injected into their brain, which caused bleeding. “Subsequent injections in patients were performed under general anesthesia and were without complication,” noted Dr. Tuszynski. One of the two patients who experienced bleeding died five weeks after nerve growth factor delivery as a consequence of the brain hemorrhage. “We examined the brain of [this] patient and found extensive trophic responses of degenerating cholinergic neurons to nerve growth factor,” which is the first time that sort of recovery has been observed in a human after such a surgical procedure, said Dr. Tuszynski. Hemorrhage in the second patient caused right hemiparesis and exacerbation of dementia-associated aphasia, after which the patient demonstrated modest improvement.

GENE THERAPY FOR NEURODEGENERATIVE DISORDERS

Dr. Tuszynski’s findings of improved PET activity and a possible effect on clinical outcome were similar to those observed after delivery of a dopaminergic growth factor, glial cell line–derived neurotrophic factor (GDNF), in a recent trial of patients with Parkinson’s disease. In that study, growth factors were restricted to specific striatal targets by continuous intraparenchymal GDNF protein infusions. Dr. Tuszynski referred to patients with either Alzheimer’s disease or Parkinson’s disease as “excellent candidates” for the nerve growth factor gene therapy approach.

“In the case of Parkinson’s disease, growth factor gene delivery could also prevent cell loss and thereby significantly reduce disease progression,” he said. “Surgical procedures already have a place in the common management of Parkinson’s disease. Growth factors, if effective, could likely have greater effects than currently employed surgical procedures. For this reason, I believe that growth factor gene therapy would also be commonly accepted for the treatment of Parkinson’s disease, if shown to be effective in larger and controlled clinical trials.” He added that a clinical trial of growth factor gene delivery for patients with Parkinson’s disease, scheduled to begin this summer, will be conducted at the University of California, San Francisco.

A PRACTICAL PROCEDURE?

Critics have questioned whether surgical treatment for prevalent neurodegenerative disorders such as Alzheimer’s disease or Parkinson’s disease would be practical, and Dr. Tuszynski wanted to address those concerns. “In the case of Alzheimer’s disease, the gene delivery procedure requires placement of a single burr hole per side of the head and a relatively brief injection,” he said. “The entire procedure can be completed in three hours. When faced with a progressive neurologic disorder, and a potential therapy that could significantly reduce cell death and improve quality of life after a brief and simple surgical procedure, I believe that this can be practical and commonly accepted.”

As for the next step in making that happen, “Future larger, placebo-controlled, blinded studies will address this possibility,” said Dr. Tuszynski. “Future studies—now in progress [at Rush University Medical Center in Chicago]—are testing a simpler form of nerve growth factor gene therapy using a new and superior gene therapy vector delivery approach.”

NR

—Colby Stong

Suggested Reading
Barroso-Chinea P, Cruz-Muros I, Aymrich MS, et al. Striatal expression of GDNF and differential vulnerability of midbrain dopaminergic cells. Eur J Neurosci. 2005;21:1815-1827.
Chen Q, He Y, Yang K. Gene therapy for Parkinson’s disease: progress and challenges. Curr Gene Ther. 2005;5:71-80.
Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease. Nat Med. 2003;9:589-595.
Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005;11:551-555.
Tuszynski MH. Growth-factor gene therapy for neurodegenerative disorders. Lancet Neurol. 2002;1:51-57.

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