Is anyone, parent or physician, brave enough to allow gene therapy in newborn babies? The answer may come sooner than we think. In Sunday’s Nature Biotechnology online, researchers led by Brian Kaspar at Nationwide Children’s Hospital, Columbus, Ohio, report remarkable success in rescuing spinal muscular atrophy (SMA) in mice. The rescue came after injecting one-day-old pups with an adeno-associated virus (AAV) carrying the gene for the survival motor neuron protein (SMN). Like human infants, mice with SMA weaken rapidly and die in infancy (their median lifespan is about 16 days compared to two to three years for normal mice). Apart from reduced stature, SMA pups treated with the virus grew strong and are still alive 250 days later, and counting. “They have, in essence, cured mice of a fatal disorder,” Alex MacKenzie, a clinician researcher studying SMA at Children’s Hospital of Eastern Ontario, Ottawa, told ARF. MacKenzie was not involved in the study, but wrote an accompanying News & Views for the journal. Kaspar and colleagues also report that the gene delivery method works in primates, raising the possibility that the therapy could be tried in humans before long. That the same virus could eventually be used to deliver genes to treat adult motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), or even neurodegenerative diseases such as Parkinson’s or Alzheimer’s, is also a possibility.

Injecting a 70- or even 40-year-old with trillions of viral particles might seem risky enough. But is the world ready to try gene therapy on newborns? That would seem to be a prerequisite, since the researchers found that delaying the therapy, for even four days, markedly reduced the efficacy. “I can see, technically, how it would be very promising. The hesitation stems from the fact that infants and children are so sacrosanct,” Mackenzie said. But when one considers the alternative—rapid deterioration in muscle control and death from respiratory failure within four to five years (18-24 months in developing countries)—then the decision may weigh less heavily. “SMA type 1 is so drastic, and these mice have lived so long, that if you were going to choose an intervention for this disorder, then this might be one to push,” suggested MacKenzie. Pharmacological approaches are being pursued but have only increased lifespan in mice to 40 days.

There are precedents that make newborn gene therapy more likely. Researchers at the Scheie Eye Institute, University of Pennsylvania, Philadelphia, recently reported success with gene-therapy in young adults to treat Leber congenital amaurosis, a severe form of childhood blindness (see Cideciyan et al., 2009). They are now recruiting for several more trials in children as young as three years old (see Jerry Mendell, at Kaspar’s own institution, Nationwide Children’s Hospital, is currently running a gene therapy trial for Duchenne muscular dystrophy in children five to 15 years old. In both sets of trials the principle is the same: use the AAV to deliver a good copy of a missing or mutated gene.

SMA is a recessive, inherited disorder. The missing gene, SMN1, plays a crucial role in RNA metabolism. It is not clear why loss of SMN1 affects motor neurons in particular, but to rescue them, Kaspar and colleagues used an AAV9 that passes the blood-brain barrier (see ARF related news story) to deliver SMN1 to the neurons. First author Kevin Foust and colleagues injected the viral particles into the facial vein of mouse pups lacking murine SMN one day after birth. They used virus expressing green fluorescent protein (GFP) as a control. Nine days later, 40 percent of motor neurons expressed GFP in the control group, and SMA was markedly increased in the brain, spinal cord, and quadricep muscles of the treated animals. Motor function in the SMN-treated pups developed similarly to that in wild-type animals. By day 13, almost all the SMN-treated animals could right themselves, whereas only 20 percent of GFP-treated controls could. While the control animals were dead by day 22, SMN-treated animals continued to gain weight until day 40 and lived far beyond. One died at day 97 from causes that appear unrelated to SMA, four animals were sacrificed between day 90 and 99 for analysis, and the remaining six animals were still alive 250 days after birth.

Foust et al. reported that transmission in the neuromuscular junction, which is compromised in SMA animals, was fully rescued in SMN-treated mice 90-99 days old. Electrophysiological measurements revealed conductance in the tibalis anterior muscle that was indistinguishable from control mice (~19 nA). The conductance is a factor of the number of synaptic vesicles released from motor neurons and the amplitude of the muscle response to release from a single vesicle. While the former was reduced in the rescued animals, the latter was increased to compensate. This suggests that neurotransmission in the nerves is not completely normal, but good enough to spur the muscles into action. Neurofilament accumulation, a hallmark of SMA, was also dramatically reduced in the treated animals.

The most obvious shortcoming was that the mice did not grow to normal size. Their weight stabilized by day 40 at around 17 g, about half the weight of normal mice. The authors suggest two explanations for the stunted growth. One is that SMN has a developmental role in the womb. The other, perhaps more likely explanation, is that transfection of all motor neurons is required for a mammal to reach its full growth potential. This could possibly be addressed by advances in vector design, the authors write.

To test the waters of primate therapy, Foust and colleagues injected a thousand trillion GFP-expressing AAV9 particles into the vein of a cynomolgus monkey one day after birth. On day 25, they found robust expression of GFP in dorsal root ganglia and motor neurons of the spinal cord. “This finding demonstrates that early systemic delivery of scAAV9 can efficiently target motor neurons in a nonhuman primate,” write the authors.

The incidence of SMA is about 1:6,000 to 1:10,000 live births. Most affected babies appear perfectly healthy initially, but begin to show signs of deterioration over three to six months. Unfortunately, this timing bodes ill for early diagnosis, or a treatment that must be started immediately. Fortunately, the vast majority of SMA cases result from the loss of a single cytosine in exon 7 of both copies of the SMN1 gene, which means a simple genetic test based on the absence of this single nucleotide could be used for high-throughput screening. As MacKenzie writes in his News & Views, several groups are working on developing such a screen.

As for adult diseases, such as AD or PD, MacKenzie said the AAV principle could be put to work. One of many questions would be what gene to load onto it for expression.—Tom Fagan


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News Citations

  1. Virus Slips Through Blood-Brain Barrier to Deliver the Gene Goods

Paper Citations

  1. . Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Hum Gene Ther. 2009 Sep;20(9):999-1004. PubMed.

External Citations

  2. gene therapy trial

Further Reading

Primary Papers

  1. . Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010 Mar;28(3):271-4. PubMed.
  2. . Genetic therapy for spinal muscular atrophy. Nat Biotechnol. 2010 Mar;28(3):235-7. PubMed.