Jennie and Gary Landsman and their family did extensive research to identify scientists and clinicians who can best help their young sons, Benny and Josh, who are afflicted with Canavan disease. They discovered a promising experimental gene therapy program right here in New Jersey.
“We reached out to multiple physicians and researchers,” Rise Landsman, Gary’s mother, said. “We have happily connected with Dr. Paola Leone, at Rowan, whose goal is to translate successes of the lab into the clinical setting.” Dr. Leone directs a research team at the Cell and Gene Therapy Center at Rowan University School of Osteopathic Medicine in Stratford.
Canavan is a disease that strikes Jews disproportionately. “The disease has been reported worldwide, but is more frequent in Ashkenazi Jewish populations,” according to www.orpha.net, a website about orphan diseases, a category that includes Canavan. “The incidence of severe CD in the non-Jewish population has been estimated at approximately 1:100,000 births,” it continues. “If both parents are of Ashkenazi Jewish descent, the incidence is 1:6,400 to 1:13,500 births.
“The prevalence of Canavan disease in the general population is unknown. Among people of Ashkenazi Jewish descent, the disease affects approximately 1 in 6,400 to 13,500 people, making 1 in every 40 to 58 Ashkenazi Jews a carrier.”
Canavan disease is caused by a mutation in the gene that makes the enzyme aspartoacylase, or ASPA, which normally breaks down the chemical N-acetyl aspartic acid, called NAA. Most people have two functional copies of that gene. A person who carries one copy of the mutated gene is a carrier with no symptoms. When both parents are carriers, there is a 25 percent chance of a child inheriting two copies of the flawed gene. When that happens, the child does not have that critical enzyme, and instead has Canavan disease.
When the enzyme ASPA is missing, there is a buildup of NAA in the brain; that is a hallmark of Canavan. The chemical dysfunction affects the way neurons in the brain develop, including the myelin coating on nerve fibers, which is not being laid down properly.
Because the gene mutation leads to the absence of an enzyme that is critical to brain development, researchers have attempted enzyme replacement therapy. That type of therapy works well for another genetic disorder, Gaucher disease, whose sufferers also do not have a critical enzyme. That approach has not been successful for Canavan, however, because it has not been possible to get the enzyme to enter affected brain cells.
Because the root cause of the disease is a defect in the DNA sequence that encodes the ASPA gene, the best hope to correct that defect is through gene therapy. Dr. Leone and her research team, who are pioneers in this area, devised a way to use a virus to carry the healthy DNA sequences into the brains of Canavan patients. (The viruses used to transport the therapeutic genes in these experiments are altered so they do not cause disease.)
In Dr. Leone and her colleagues’ original study, published in 2002, Adeno-associated virus (AAV) carrying the ASPA gene was injected into the brains of 21 patients with Canavan disease. A follow-up study of these patients, published in 2012, showed that the treatment produced no adverse effects; that finding is critical to any experimental procedure to be used on human subjects. The research also showed a decrease in the chemical NAA, thought to be a factor in causing the Canavan defect, and it showed other improvements, including “slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.”
That study provided a glimmer of hope for the success of gene therapy in Canavan patients.
A more recent study published in 2016, conducted by Paola Leone and collaborators in four prominent research centers, showed how NAA affects the development of brain cells in a mouse model of Canavan disease.
“Dr. Leone’s team is currently testing the most advanced gene therapy vector in the world for Canavan disease, which was recently developed by her collaborators at UNC,” an online description of Leone’s research says. “Unlike other gene therapy options, this newest gene therapy vector specifically targets the cells affected in Canavan disease and holds a real promise for finally curing the disease.”
“Fifteen years ago, Paola was involved in research introducing the AAV vector into six holes in the brain. She also worked with murine models,” Rise said. (Murine models are mice.) “She knows where to go, now using two holes” instead of six, “for viral vectors to get in.”
“Paola Leone’s project will cost $1.2 to $1.5 million,” she continued. “She is submitting an application to a foundation. Once it’s approved, we hope that my grandsons will be part of the research.”
When new therapies are developed, there are many steps needed to test the procedures before human subjects may be used. Under some circumstances it is possible to fast-track the process, and that is the goal that Dr. Leone and the Landsmans and Rosenblums share. They have no time to waste; as the boys get older, the likelihood that they can be cured worsens.
“You can ask for compassionate use, for a small group of subjects,” Rise said. “With orphan diseases it’s the families that get movement, raise the funds, speak to politicians, get expeditious approval of the FDA.” Orphan diseases are rare diseases that affect fewer than 200,000 people. The Orphan Drug Act of 1983 provides a mechanism to facilitate research on these diseases.
“We do not want to wait for an NIH trial, as it could take forever,” Rise continued. “We are hoping to move things along. The government won’t fund a compassionate use submission,” thus the urgent need for private funding.
Just last week, the FDA approved the first gene therapy treatment to correct an inherited genetic mutation, in this case in a gene that causes retinal dystrophy, a rare form of blindness. The mutated gene RPE65 can be treated by using a genetically engineered virus carrying a healthy version of the gene to the retina. Clinical trials showed improved vision in 27 out of 29 patients who got the treatment.
Now that the dam of gene therapy is open for one genetic mutation, there is hope for success in curing other genetic diseases as well.
“Through our grandsons we will find a cure for Canavan, and we hope that our grandsons will be beneficiaries of the research,” Risa said. “Each success is inspiring, and engenders greater hope in us.”
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Miryam Z. Wahrman Ph.D. is professor of biology at William Paterson University of New Jersey, and author of The Hand Book: Surviving in a Germ-Filled World, a book that provides handy tips on how to reduce the risk of infectious disease, which is especially important advice during cold and flu season.