Gene therapy makes major stride in ‘Lorenzo’s Oil’ disease

In the third gene-therapy success of recent weeks, French researchers have arrested the progression of the rare and fatal degenerative disorder adrenoleukodystrophy, which was at the heart of the popular movie “Lorenzo’s Oil.” The disease has stabilized in two boys who were 7 years old when the therapy was performed two years ago, the team reported today in the journal Science.

“This is a disease that never, ever stabilizes” on its own, said Dr. Katherine A. High of the Children’s Hospital of Philadelphia, who was not involved in the research. “The fact that they were able to achieve that means they are getting a therapeutic effect.”

This is the fifth disease for which gene therapy has been shown to be beneficial, said Dr. Theodore Friedmann of UC San Diego, who was also not involved. “That’s a major achievement for a field that has been in the clinic for only 18 or 19 years. . . . This is a new form of medicine and deserves to be seen as such.”

The French team has already treated a third boy who has the disease. Although results are not yet available in that case, the team plans to expand the trial to others, including older men with a milder form of the disease.

Adrenoleukodystrophy, commonly known as ALD, is identified in about 120 young boys in the U.S. each year. Those born with the defective ALD gene appear to be normal until about age 5, “when a really catastrophic process of progressive, relentless demyelination [of the brain] sets in that leaves them vegetative or dead within one to two years,” said Dr. Florian Eichler of Massachusetts General Hospital, an expert in the disease. “This is as bad as neurological disorders get.”

If the disorder is identified before brain deterioration begins, the concoction known as Lorenzo’s oil — a mixture of fats from olive and rapeseed oils that purportedly reduces abnormally high levels of damaging long-chain fatty acids in the brain — can delay the disease’s progress somewhat.

Once deterioration begins, however, the only option has been a bone marrow transplant. For the few children who have a closely matched sibling, the procedure can arrest progression. A transplant from a less closely matched donor can help, but can also have severe side effects. Some patients, for example, must use a wheelchair as a result of the procedure.

The new research was conducted by a team headed by Drs. Nathalie Cartier and Patrick Aubourg of Paris Descartes University, who have been involved in previous successful studies of severe combined immunodeficiency disease.

They took the healthy form of the ALD gene and inserted it into HIV — the AIDS virus — that had been “defanged” so that it could no longer cause disease. HIV, from the lentivirus family, has been of great interest to gene therapists because it can insert genes into cells that are not actively dividing. Previous viruses used as delivery systems have only been able to insert genes into cells that are dividing.

The HIV delivery system may also be safer. Mouse retroviruses that have been used in previous studies of gene therapy can activate genes near where the added gene is inserted into the chromosome, potentially creating problems. That may be why a gene-therapy treatment for X-linked severe combined immunodeficiency, or SCID, caused some cases of leukemia. Lentiviruses are much less likely to turn on unwanted genes.

Despite years of research, this is the first time that a lentivirus has been used in a human trial. Aubourg and his colleagues chose it because it introduces the desired gene into a higher proportion of cells.

The French team isolated bone-marrow stem cells from the two boys, then used the virus to introduce the healthy ALD gene. They then did the equivalent of a bone-marrow transplant, destroying the boys’ marrow and introducing the modified cells, which proliferate to form new marrow. About 15% of the cells began producing the desired protein, and production has persisted for the two years of follow-up.

Fifteen percent may not seem like much, but “it is a level that would be therapeutic for a variety of other diseases, like sickle cell disease,” said Dr. Donald Kohn, a gene-therapy researcher at UCLA.

He noted that the first successful treatment for SCID in Milan got production of the desired gene in only “1% of cells at best.”

The effects on the disease were about the same as those from a successful bone-marrow transplant using closely matched cells, Aubourg noted.

“That’s good news because many patients don’t have access to bone-marrow transplants [that are good matches], and it is not an innocuous procedure,” Friedmann said.

The team documented its success in arresting the disease in a variety of ways, and was able to demonstrate that the procedure was safe.

In the last two weeks, researchers have reported using gene therapy to treat an eye disease called Leber’s congenital amaurosis and to rejuvenate human lungs that would otherwise be unfit for transplantation — although treated lungs have not yet been transplanted into humans. Two forms of SCID had previously been cured, and now ALD.

Gene therapy “has crossed a threshold, scientifically and medically, and also in credibility,” Friedmann said. These studies “are not hype; they are not hyperbole. They really are providing treatment for sick people.”

See here for the official release.

Clinical Tests Begin on Medication to Correct Fragile X Defect

NIH-supported scientists at Seaside Therapeutics in Cambridge, Mass., are beginning a clinical trial of a potential medication designed to correct a central neurochemical defect underlying Fragile X syndrome, the most common inherited cause of intellectual disability. There has to date been no medication that could alter the disorder’s neurologic abnormalities. The study will evaluate safety, tolerability, and optimal dosage in healthy volunteers.

The work is the outcome of basic research that traced how an error in the fragile X mental retardation gene (FMR1) leads to changes in brain connections, called synapses. The changes in turn appear to be the mechanism for learning deficits in Fragile X syndrome. The new trial tests Seaside Therapeutics’ novel compound, STX107, that selectively and potently targets the synaptic defect.

Thomas R. Insel, M.D., director of the National Institute of Mental Health, said, “This project is the culmination of years of fundamental research, first identifying the genetic mutation and later deciphering the biochemical consequences of this mutation. Now, with the initiation of this first clinical study, we move one step closer to understanding how this novel candidate may play a critical role in improving the lives of individuals with Fragile X Syndrome.”

Randall Carpenter, M.D., president and chief executive officer of Seaside Therapeutics, and Mark Bear, Ph.D., Seaside’s scientific founder, are leading the research. Dr. Bear is a Howard Hughes Medical Institute investigator and a professor of neuroscience at the Massachusetts Institute of Technology, Cambridge, Mass.

The National Institute of Mental Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Neurological Disorders and Stroke (NINDS) have provided grant support. Private foundations providing funding include the advocacy groups Autism Speaks and FRAXA Research Foundation.

Fragile X syndrome is the most common inherited cause of intellectual disability, affecting an estimated 1 in 4,000 males and 1 in 6,000 females.

The syndrome causes a range of developmental problems, including learning disabilities and cognitive impairment. People with Fragile X syndrome may have anxiety and attention deficit hyperactivity disorder. About one-third of males with Fragile X syndrome also have autism or autistic-like behavior that affects communication and social interaction. Usually, males, who have only a single X chromosome, are more severely affected than females.

People with Fragile X have DNA mutations in the FMR1 gene that, in effect, turn off the gene. Research in recent years by Dr. Bear and colleagues has identified the molecular consequences of this silencing of FMR1. Normally, the protein product of the FMR1 gene acts to dampen the synthesis of proteins at synapses that are stimulated via a specific class of receptors on brain cell — metabotropic glutamate receptors (mGluRs). Without the brake provided by FMR protein, synaptic protein synthesis is excessive and connections do not develop normally.

This basic research provided the basis on which to develop medications that could correct the defect.

The current study will focus on a compound, designated STX107, that selectively inhibits one type of mGluR receptor, mGluR5. Evidence in mice with Fragile X-like symptoms suggests that reducing levels of mGluR5 can restore normal synaptic protein synthesis and improve function.

The initial phase 1 study of STX107 will involve healthy volunteers. If results suggest that the medication is safe and tolerable, the study will progress to a phase 2 test of dosage and efficacy in adults with Fragile X syndrome. If STX107 shows promise in adults, the compound will be assessed for pediatric safety (with funding from the Best Pharmaceuticals for Children Act [http://bpca.nichd.nih.gov/about/index.cfm] through NICHD) prior to initiating clinical trials in children.

For more information on clinical trials related to Fragile X syndrome, go to http://clinicaltrials.gov/.

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit www.nimh.nih.gov.

The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s Web site at http://www.nichd.nih.gov.

NINDS (www.ninds.nih.gov) is the nation’s primary supporter of biomedical research on the brain and nervous system.

The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.