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BERLIN, Germany — In early trials, gene therapy and neural stem cell transplantation appear to be promising complementary approaches to treating multiple sclerosis (MS). So reported a team of Italian researchers led by Gianvito Martino, MD, who discussed the preliminary results at this year's Annual Meeting of the European Neurological Society here.

Speaking at the Presidential Symposium, Dr. Martino said preliminary data suggest that gene therapy and neural stem cell transplants can be used in different combinations and at different times in the disease process to reduce inflammation, demyelination, and loss of axons.

“MS is a local ‘process’ in which the reparative phase is ‘disordered’,” Dr. Martino told symposium attendees. Systemic therapy has several limitations, he said, including the inability to reach local sites of disease in the central nervous system (CNS), due to its inability to cross the blood-brain barrier.

Dr. Martino and his colleagues from the Department of Neuroscience at San Raffaele Scientific Institute in Milan, Italy, are conducting gene therapy studies in animals, using biological vectors engineered to express anti-inflammatory cytokines and neurotrophic growth factors. They are also implanting neural stem cells in animals with experimentally induced autoimmune encephalomyelitis (EAE), an experimental model that mimics MS.

To date, early results suggest that the two techniques may be complementary, he noted. Gene therapy seems to induce adult progenitor cells to proliferate and migrate, whereas stem cell transplantation holds promise for remyelination.


The Italian investigators developed a delivery system for gene therapy that relies on intrathecal injections of an adenovirus engineered with anti-inflammatory cytokines or neurotrophic growth factors. A single injection of the adenoviral vector can sustain transgene expression for more than five months, Dr. Martino said.

He and his colleagues found that this approach could provide a reliable delivery system, using the cerebrospinal fluid (CSF) to infect ependymal, choroidal, and leptomeningeal cells. Then, they conducted experiments using vectors that express different cytokines – interleukin-4 (IL-4), or interferon (IFN) gamma – administered after the experimental disease had been induced.


Dr. Martino noted encouraging results with the adenovirus delivery system to deliver fibroblast growth factor-2 (FGF-2). There was a reduction in myelin damage and axonal loss when adenovirus was used to deliver FGF-2 during the formation of an acute lesion. The research team also attempted to use this delivery system to bring growth factors to established lesions, hoping for neuroprotection and remyelination, but they could not accomplish this.

Dr. Martino acknowledged that, although his team has achieved a persistent therapeutic effect using a single administration of adenovirus plus FGF-2, there are still several limitations to be overcome before this approach is ready for human trials. He stressed that the research is still in an early phase and that results with animal studies do not easily translate to human trials.


But, Dr. Martino continued, there are several reasons to continue exploring this complementary approach. When neural stem cells are injected into the CSF, they seem to “sense where the MS lesions are,” Dr. Martino said. “At least three experiments using neural stem cells have demonstrated impressive results.”

In these experiments, mice with EAE were treated with neural stem cell transplants and compared with untreated EAE mice as controls. “Neural stem cell transplantation did not work on inflammation, but it did block axonal loss,” Dr. Martino said. “The neural stem cells entered the brain through the CSF and spread only to areas of axonal loss. Fifty percent of the treated animals recovered completely.”


Dr. Gianvito Martino said preliminary data suggest that gene therapy and neural stem cell transplants can be used in different combinations and at different times in the disease process to reduce inflammation, demyelination, and loss of axons.

These results suggest that localized delivery of gene therapy and stem cell transplants may offer respective benefits in MS. Gene therapy delivered FGF-2 and IL-4, leaving olicodendrocyte precursors as survivors. Neural stem cell transplants, in contrast, could reverse demyelination. If these preliminary results are borne out, the therapies will be studied in humans.


Dr. Richard Ransohoff: “I think it is quite plausible that one may need to condition both the environment and the cellular composition of MS lesions to achieve a better outcome for MS patients.”


In a separate interview, Richard Ransohoff, MD, commended Dr. Martino and his colleagues on their accomplishments, but also noted that these approaches remain experimental and are a long way off from clinical application. Dr. Ransohoff is a staff neurologist at the Mellen Center for MS Treatment and Research and staff scientist in the neurosciences department of the Lerner Research Institute at The Cleveland Clinic Foundation in Ohio.

“This type of gene therapy is still more of a research tool than a near-term alternative for treatment of MS, “Dr. Ransohoff said. “We need to keep a laser-like focus on the MS patient, who is typically a neurologically intact woman aged 25 to 30. This woman has an uncertain outlook regarding the progression of disease, and the likelihood that we will be injecting genetically engineered viruses and neural stem cells into her brain in the near future is low.”

That said, Dr. Ransohoff continued, “the work by Dr. Martino's team represents a real and impressive advance, but also reveals an equivalent number of roadblocks.”


It is not widely recognized how difficult it is to achieve robust gene expression without causing inflammation in the brain, he continued. “This can only come from a great deal of dedicated tinkering with the virus, which will have to continue for a long time until there is sufficient, sustained gene expression to be clinically meaningful. Dr. Martino's research team has made a major leap in that they now can produce gene expression over several months. People have gone from a few days to a few weeks, and with these studies, to a few months,” Dr. Ransohoff said.

Dr. Martino tested IFN gamma in EAE and showed that EAE was reduced in severity and why this occurred, he continued. “This is an extremely clever and flexible approach to getting a cytokine where you want it, when you want it. This type of approach can tell us a great deal about the disease process.”

Dr. Ransohoff cited recent reports in Nature Medicine by separate groups of Australian and German researchers suggesting that factors such as leukemia inhibitory factor and ciliary neurotrophic factor can regulate oligodendrocyte survival without causing inflammation. This suggests a different growth factor for future study.

“I think it is quite plausible that one may need to condition both the environment and the cellular composition of MS lesions to achieve a better outcome for MS patients. Both cells and growth factors are needed to repair the nervous systems of MS patients. Dr. Martino's work is an extremely important contribution to this field,” Dr. Ransohoff said.

Dr. Ransohoff ended the interview by recalling the tragedy at the University of Pennsylvania where a young patient died after receiving an adenovirus vector to deliver gene therapy. That misfortune underscored the fact that the use of gene therapy for young adults with MS is going to be “a long, slow process.”


  • ✓ A team of Italian researchers led by Dr. Gianvito Martino reported that neural stem cell grafts and gene therapy – used in different combinations and at different times – showed impressive results in animal models of multiple sclerosis.
  • ✓ In experiments with mice, gene therapy using an adenodelivery system reduced myelin damage, while neural stem cell transplants seemed to block axonal loss.
  • ✓ Dr. Richard Ransohoff, a leading MS clinician and researcher, praised the techniques used by Dr. Martino's team as “advances,” but noted they are useful as research tools and are not ready for use in human trials.