Promise of Outpatient Brain Gene Therapy is One Step Closer

In the October 17 issue of Nature Methods, researchers at Thomas Jefferson University describe how they can transfer genes into brain neurons intravenously, using a viral gene delivery vehicle (vector) that causes no side effects.

They say their findings potentially represent a major advance in the effort to treat brain disorders with therapeutic transgenes, or external genes – suggesting that gene therapy to the brain could be given to patients on an outpatient basis, simply by IV administration into the arm.

All other viral gene delivery vectors tested to date must be delivered directly into the brain and they may elicit immune responses that impair their effectiveness, the researchers say. The immune system may recognize and eliminate brain cells that have been genetically modified, and it can mount an antibody response against the virus vector itself that limits how often that therapy can be given.

“Our unique and simple method avoids these problems,” says the study senior investigator, David Strayer, M.D., Ph.D., Professor of Pathology, Anatomy & Cell Biology at Jefferson Medical College of Thomas Jefferson University. “We don’t have to enter the skull and inject into the brain, and we see absolutely no immune response or any other side effects in our animal experiments.”

Using such a method, it may be possible, for example, to treat diseases thought to be due to excessive oxidative damage to neurons and neuron proteins, such as early Alzheimer’s disease or Parkinson’s disease, with extra genes that limit oxidative damage to brain neurons, he says. “This is theoretical of course, but through our method of delivering genes directly to neurons, we might be able to arrest or slow the progression of a number of neurodegenerative disorders, or potentially correct selected disorders that are due to one faulty gene,” Dr. Strayer says. “Our approach also allows us to offer gene therapy as often as needed – not just one or two times.”

The advance was made possible by two major discoveries. One was use of vectors derived from recombinant SV40 viruses, which have been extensively tested by Dr. Strayer, and the other is use of a sugar alcohol, mannitol, that relaxes the blood-brain barrier so that the vector can pass through. The idea to combine these two approaches came from first author Jean-Pierre Louboutin, M.D., Ph.D., a research associate in the Department of Pathology at Jefferson.

“Mannitol is commonly used in a clinical setting to reduce intra-cranial pressure during head trauma,” he says. “It loosens the tight vascular barrier that only allows small molecules like oxygen to move from the blood into the brain. We thought it might help our viral vectors pass through – and it does.”

Using mannitol before delivery of the gene-laden SV40 viral vectors in mice also directs most of the viral particles into the brain, instead of to other parts of the body, for reasons that the researchers do not yet understand, Dr. Louboutin says. “It makes delivery of the genes into brain tissue very efficient.”