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Gene Therapy Holds Hope for Disease

In the budding field of gene-therapy, a number of diseases and areas of the body have undergone tests and treatment — but not, until recently, the brain.

Canavan patients are the first human beings to receive gene therapy in the brain, and not only has this new form of gene therapy greatly surpassed past efforts at such treatment in Canavan patients, but it also shows great promise for progress in therapy for Parkinson’s disease and Alzheimer’s.

Canavan disease is characterized by a deterioration of the white matter in the brain, as well as hindrance of growth of the fatty myelin sheath around nerve fibers. Children suffering from Canavan disease are often blind, speechless, have poor head control and suffer from megalocephaly (an abnormally large head), seizures and hearing loss. Most die before their 10th birthday.

This new gene therapy for Canavan patients has evolved dramatically in the past year. Researchers and doctors have devoted years to the development of the non-pathogenic adeno-associated virus, or AAV, and in the past year attempted planting the virus into the brains of patients. To treat patients, minuscule holes are drilled into the brain, and catheters send the virus into each part of the brain through viral vectors.

Doctors and researchers expect the new virus to produce the enzyme that patients lack — aspartoacylase, or “aspa,” which is responsible for removing cellular waste from the brain. A mutation in a gene accounts for Canavan patients’ lack of aspa, which is supposed to break down N-acetyl aspartate, or NAA.

“If you have that enzyme, it breaks [NAA] down and everything is normal,” said Dr. R. Jude Samulski, director of the University of North Carolina Gene Therapy Center. “If you don’t, NAA accumulates in the white matter of the brain and ends up being a toxic compound,” which in turn causes a hole to form where the white matter should be.

“We’ve been developing AAV with hopes that it is inherently safe,” Samulski said. “[The virus] has no track record of being harmful.” Nonpathogenic means that people have been infected with this virus before and there has been no disease associated with it.

Helene Karlin, president of the New York-based Canavan Foundation, has an 8-year-old daughter, Lindsay, who has Canavan disease. Karlin boasted of the huge improvements that researchers and doctors have made with the new therapy. Lindsay was one of five children treated, said Karlin, and there has been an increase in the myelin in her brain.

“She’s improving and improving and improving,” Karlin said. Such progress, she said, “correlates with the fact that she’s looking much better.”

Dr. Paola Leone, director of the Cell and Gene Therapy Center at the Robert Wood Johnson Medical School in New Jersey, spearheaded this progress. Leone and a group of 16 other investigators and surgeons have been working diligently on refining and perfecting the therapy. Researchers, such as Samulski at the University of North Carolina at Chapel Hill, created this new therapy in the lab. Leone was the first to attempt the therapy on human beings.

“She’s changed the course of this disease for these kids,” said Karlin of Leone.

Leone recruited researchers at Chapel Hill, including Samulski, to work with her and to develop a vector that could be used clinically in human beings. Previously the virus was only tested on rodents, dogs and monkeys.

“We originally developed this vector to work for people who have uncontrollable seizures,” said Samulski, who went to graduate school with the goal of developing a viral vector and has been plugging away with refinement of AAV for the past 20 years. At least such research is “leading in the gene-therapy community today.”

“We have pioneered the vectors, the delivery system,” Samulski said. “Our 20 years [working with the vector] have been in optimizing them in being a safe delivery system for the brain…. We are the component in optimizing the shuttle.”

Leone is dealing with the neurological end of the treatment. She is the one who operates on the patients and has immersed herself in the cause because it has become a passion for her, according to Karlin.

“She’s been willing to commit herself in a way that nobody else out there has done,” said Karlin of Leone, who has pictures of her patients hanging in her office.

The research and therapy comes with a hefty price tag, but Leone received a $2 million grant from the National Institutes of Health this year.

“The NIH is recognizing that this research has tremendous potential because they feel the value of this research is that it can be applicable to other diseases as well,” Karlin said.

Each surgery is costly, as is the research. “We hold our breaths when they’re putting [the virus] into the brain,” Samulski said. “It’s a financial burden, but it’s a justified burden.”

Parents of Canavan patients are not expecting a cure for the rare genetic brain disorder anytime soon. They are, however, expecting rapid progress in the gene-therapy research for the disease, progress that can dramatically improve the lives of their children. These immediate expectations are not illusions; the astonishing leaps made in the research and actual, clinical therapy for the disease in the past year rekindle hope for what would have seemed hopeless only a few years ago.

While gene-therapy research and trials have been ongoing for almost a decade, the previous attempts only helped sporadically. The newest therapy, only recently approved by the Food and Drug Administration, shows that Canavan children have no loss of myelin levels, and other changes such as improved motor skills.

There are three primary goals of researchers, according to Samulski: spreading the gene to as many cells in the brain as possible, the efficiency of delivering the payload of the virus and the proper functioning of the payload so that patients don’t encounter further problems.

As for future developments, stem cells could play an integral role in treatment. According to Karlin, the new vector stabilizes the brain of Canavan patients but does not repair damage that is already done. Stem cells could fill that gap.

For now, however, researchers and doctors are continuing their efforts to fulfill their immediate goal of refining the therapy and operating on more patients.

For people who may shun or fear gene-therapy, said Samulski: “As a moral obligation we need to go forward. As a community we need to go forward.”

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