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Gene Therapy in SMA Mice Has Experts Talking About Potential for Human Trials and Genetic Screening


doi: 10.1097/01.NT.0000383482.61535.6e
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In separate studies using mouse models of spinal muscular atrophy, systemic delivery of gene therapy for spinal muscular atrophy (SMA) alleviated symptoms and prolonged life.

Two recent studies, one presented at the AAN annual meeting in Toronto in April and another published in the March Nature Biotechnology, indicate that systemic delivery of gene therapy for spinal muscular atrophy (SMA) can alleviate symptoms in a mouse model of the disease. The results set the stage for further preclinical work to determine the potential for gene replacement strategies to treat SMA in humans, and strengthen the case for genetic screening for the disease.

Previous studies confirmed that the gene mutated in SMA, called SMN1 (survival of motor neuron gene) could be successfully delivered via intramuscular injection of a viral vector, leading to uptake within motor neurons and production of the SMN protein. But systemic delivery would be needed to have any important clinical effect, and it is that step that the current studies address.

The SMN protein is vital for RNA processing. Two genes encode the protein, SMN1 and SMN2. But the SMN2 gene is missing a critical exon, and provides very little functional protein. SMA occurs when a child inherits no working copy of SMN1, either due to deletion or mutation. One in 30 individuals carries a mutant or deleted form of SMN1. With an incidence of 1 in 10,000 live births, SMA is one of the most common autosomal recessive genetic disorders.

The vector used in both studies was the so-called self-complementary adeno-associated vector 9, or scAAV9, chosen because of its increased ability to transduce neurons in the CNS, predominantly spinal cord motor neurons, according to Chiara Valori, PhD, lead investigator of the study presented at the AAN annual meeting. Dr. Valori is a post-doctoral research associate in the Department of Neuroscience at the University of Sheffield, United Kingdom.

Injections in both studies were done in mice lacking functional SMN, which usually die within two weeks of birth. Injections were done within the first several days of life, a critical window for scaAAV9's ability to cross into the CNS and transduce motor neurons. Each animal received a single intravenous injection.

Mice injected with the SMN gene did better on several tests of motor performance, including decreased righting time and ability to orient correctly, compared to untreated litter mates.



More spectacularly, “lifespan was significantly and dramatically extended,” Dr. Valori said. In her experiment, mice lived to an average of 83 days, “and most importantly, apart from the first mouse, for which we couldn't confirm transduction, the other mice didn't die because of SMA-like symptoms.”

Results in the second study were even more dramatic. While no untreated animal lived past 22 days, no treated animal died before 97 days; and even that one probably died for reasons unrelated to the effects of SMA. While some animals were euthanized before 100 days for study, six more were still alive 250 days after birth, when the paper was submitted for publication.

That study, led by Kevin Foust, PhD — a post-doctoral fellow at the Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital in Columbus, OH — also showed that while animal body weight remained under that of unaffected controls, it nonetheless increased steadily throughout the lifespan. Electrophysiologic measures showed normalization of endplate currents in treated mice.

Dr. Valori did note some adverse effects of treatment, specifically hyperactivity of the mice, enlargement of the heart, and some patchy interstitial fibrosis in the ventricle, which is still under investigation. Both groups noted necrosis of the tips of the ears. Dr. Foust said that vascular endothelium is transduced by the virus, and that there is no vasculitis in other extremities, including the tail and hind paws. He speculated that the effect in the ears may be due to a lack of transduction there, since the ear vasculature develops after the time of viral injection.

Dr. Valori said that the results she presented may provide the rationale for a clinical trial. But, she added, “we are fully aware that further investigations are needed before translating this approach into patients.”

One critical question is just how long the window of opportunity is open for viral injection. Dr. Foust showed that in mice, it closes rather quickly — virus injected at day 1 or 2 transduced mostly neurons, but by day 10, injections led to predominantly glial transduction. “Future studies in nonhuman primates will further elucidate a therapeutic window more relevant to human therapy,” he said.

His group has taken a first step in that direction, by showing that injecting the vector with a reporter gene into a newborn macaque on day 1 led to “robust” gene expression within the dorsal root ganglia and motor neurons “along the entire neuraxis.” “This finding demonstrates that early systemic delivery of scAAV9 can efficiently target motor neurons in a nonhuman primate,” according to Dr. Foust.

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Two experts on SMA were enthusiastic about the results of the two studies. Raymond Roos, MD, the Marjorie and Robert E. Straus Professor in Neurological Science in the Department of Neurology at the University of Chicago Medical Center, said: “Here we have this unbelievably desperate disease, and the possibility of an effective treatment and cure. I can't wait to see human trials.”

These results will add to an ongoing debate about screening for SMA in newborns and for carriers in the general population, said John Kissel, MD, professor of neurology at the College of Medicine at Ohio State University. With a carrier frequency of 1 in 30, and the costs of single-gene tests plummeting, the logic is compelling. “I think this will help” make the case for widespread screening, at least of newborns, he said.

The challenge in newborns is that making the clinical diagnosis at birth can be difficult. “Some of the mothers swear their child is normal at birth,” but the child begins to decline shortly afterward. “By the time the neurologist sees them, most of the babies are devastated.”

But, Dr. Kissel pointed out, a positive gene test prenatally or even at birth would still raise hard questions. “The catch is that if you identify a presymptomatic baby, is the FDA going to let you give a gene based therapy?” Waiting until symptoms develop may not be an option, if the AAV vector works in humans the way it does in mice.

“Will it be effective if given at three or six months or later in life?” Dr. Roos asked. “We have no good primate data yet, so we don't really know that.” However, he said, there are many different types of AAV vectors waiting to be analyzed, and there may be some among them able to transduce motor neurons later in development.

And unlike the hype of adenovirus-mediated gene therapy of a decade ago, which led in some cases to premature and even disastrous therapeutic trials, “there is no question” that adeno-associated virus is the appropriate vector to try, he said, with its ability to specifically target motor neurons and its highly favorable safety profile. “The field is maturing,” Dr. Roos said. “I'm very optimistic.”

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• Foust KD, Wang X, McGovern VL, et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol 2010; 28(3):271–4. 2010; E-pub 2010 Feb 28.
    ©2010 American Academy of Neurology