First Use of a Gene Therapy Shows Promise Against Fatal Childhood Disease

Released: 12/19/2012 10:30 AM EST
Embargo expired: 12/19/2012 2:00 PM EST
Source Newsroom: Rutgers Biomedical and Health Sciences
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Citations Science Translational Medicine (4, 165ra163 (2012), 12/19/2012)

Newswise — STRATFORD, N.J. – Research led by Paola Leone, PhD, of the University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine (UMDNJ-SOM), demonstrates the long term safety and benefit of a virus-based gene therapy that has been applied for the first time in a clinical setting. This novel therapy was used to treat young patients with Canavan disease, a devastating inherited neurological condition that typically takes a child’s life by age ten. Results of the study have just been published in the journal Science Translational Medicine, in an article that describes this first clinical application of a viral-based gene therapy for a neurodegenerative/neurological disorder.

The symptoms of Canavan disease usually begin to appear by the time a child is six months old. Myelin, which in a healthy child coats nerves throughout the body, does not form properly within the brain. Over time, the brain then atrophies, typically causing symptoms that include severe cognitive and motor delay, epilepsy and ultimately death. The disease results from a defect in a single gene, giving researchers the hope that by targeting and replacing that gene in patients with the mutation, they might find a way to counteract the disease’s effects.

The team led by Dr. Leone, who is an associate professor of cell biology at UMDNJ-SOM, implanted the ASPA gene (AAV2-ASPA) in 13 patients who were between three and 96 months of age, through use of an adeno-associated viral vector (9 x 10 to the 11th power vector genomes via intraparenchymal delivery at six brain diffusion sites). All members of the cohort were then followed for at least five years.

Adeno-associated viruses are nonpathogenic and can infect dividing and non-dividing cells (such as brain cells) and persist in an extrachromosomal state without integrating into the genome of the host cell, hence avoiding any endogenous oncogene activation. The researchers were able to adapt it in the laboratory to be an efficient delivery system for implantation of the human (healthy) ASPA gene without any possible wild-type virus contamination.

Following gene therapy, the research team detected statistically significant reductions in concentrations of N-acetyl aspartate (NAA) in several brain regions. Increased concentrations of NAA, an amino acid that affects central nervous system metabolism, are a primary marker of advancing Canavan disease. Other observations included less atrophy in the posterior regions of the brain than ordinarily would be expected over time. There also were indications of increased alertness following the experimental treatment, which were especially pronounced among the youngest patients in the cohort. There also was a reduction in the frequency of seizures.

Dr. Leone notes that the protocol for the trial called for the oldest within the cohort to be treated first, on the assumption that the safety of those children was least at risk. “The results, however, suggest that the greatest potential benefit comes from intervention at very young ages,” she says. “The oldest within the cohort showed the least benefit from treatment, while clinical stabilization and improvement in measures of quality of life were greatest in the youngest patients, especially those treated before age two, with no detectable reduction in patient safety. These findings strongly suggest that early detection and treatment in the neonatal period may offer the best chance of a cure.”

Dr. Leone concludes that human gene therapy requires further optimization, but has shown itself to be a viable option for treatment beginning at birth in children in whom the genetic signature of Canavan disease is found.

This was the first gene therapy study for a clinical neurological application ever approved by NIH-National Institute of Neurological Disorders and Stroke (NINDS) RO1-NS42120, with additional funding from the Canavan Research Foundation, Canavan Research Illinois, Jacob’s Cure, the National Endowment for Alzheimer’s Research, and the Ralph and Lois Silver Foundation.

About UMDNJ:
The University of Medicine and Dentistry of New Jersey (UMDNJ) is New Jersey’s only health sciences university with more than 6,000 students on five campuses attending three medical schools, the State’s only dental school, a graduate school of biomedical sciences, a school of health related professions, a school of nursing and New Jersey’s only school of public health. UMDNJ operates University Hospital, a Level I Trauma Center in Newark, and University Behavioral HealthCare, which provides a continuum of healthcare services with multiple locations throughout the State.


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