The "window of opportunity" for treating infants at risk of developing spinal muscular atrophy (SMA) may not be as narrow as some experts have feared, new experiments in mice suggest.
MDA research grantee Umrao Monani at Columbia University Medical Center in New York coordinated the scientific team, which published its results Aug. 1, 2011, in the Journal of Clinical Investigation. (See Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy.)
Monani described the “window of opportunity” as "the period between the birth of the child and the last point in time during which the motor unit [nerve cell and the muscle fibers it activates] can be rescued."
This window may be “open” for a few weeks or a few months after birth, and may extend into the period when the child begins to show SMA symptoms, Monani said. “I suspect that if the patient can be treated during this period, he or she will benefit greatly."
This finding, if confirmed in humans, further bolsters the case for newborn screening of infants for SMA. It also is good news for the potential use of several treatments for SMA currently in development.
A deficiency of SMN (for survival of motor neuron) protein, caused by mutations in the SMN1 gene, is the underlying cause of SMA types 1 through 4. The most life-threatening type, with onset in early infancy, is type 1 SMA.
Restoring sufficient levels of the needed SMN protein is the goal of many therapeutic strategies in development to treat SMA (see Many experimental SMA treatments in development).
Until now, however, it has not been clear that such a strategy would benefit babies with type 1 SMA, in whom the disease is often not diagnosed until weeks to months after they're born. Experts have speculated that, even if an SMN-elevating treatment were available, by the time symptoms appear, administering it might be too late.
These new mouse studies suggest that administering treatment after symptoms begin, even in infants with type 1 SMA, might not be too late after all.
Monani's group genetically engineered mice in which therapeutic genes for the SMN protein could be "turned on" by administering the drug tamoxifen at specific time points. The mice were given "dormant" SMN genes engineered to become active only in response to the drug tamoxifen. (This is an entirely artificial situation and does not exist in people with SMA.)
The genetic makeup of the mice, like that of human babies with SMA, caused them to be severely deficient in the SMN protein. Such mice develop typical SMA-like weakness on or about day 4 of life and generally live a total of about 17 days.
SMN rescue via gene activation markedly improved this disease course and significantly lengthened survival time.
Mice treated on day 4 and examined between days 50 and 70 showed that, except for being smaller and having a lower body weight than healthy mice, the animals could not be distinguished from healthy littermates. Their grip strength, ability to stay on a rotating rod, and other tests showed that the treated animals performed equivalently to healthy mice. Median survival time was 139 days.
Inducing SMN production on day 6 or later resulted in a much more modest impact on survival and motor function. No benefit was seen in mice not treated until day 10.
Monani believes that the day-4 to day-8 time period in mice probably corresponds to weeks to months after birth in humans.
Monani says it is clear that, while treatments to raise levels of the crucial SMN protein can be administered after birth and after symptom onset in SMA, it's likely that the earlier they're administered, the better the outcome will be.
"I think it would benefit the community greatly to establish routine newborn screening for SMA" to identify affected infants as early as possible, he said. A pilot study of newborn screening in SMA was recently funded.
And, MDA research grantee Kathryn Swoboda at the University of Utah is testing sodium phenylbuturate, a drug that may increase SMN levels, in presymptomatic infants at risk of developing SMA. This trial is designed to identify babies with SMA prior to symptom onset through genetic testing, after SMA has previously been diagnosed in an older sibling.
For details of this study, see Study to Evaluate Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy (STOP SMA); or enter NCT00528268 into the search box at ClinicalTrials.gov.
Monani said an important next set of MDA-supported experiments now under way will help determine whether SMN-elevating treatments need to be given chronically (over a long period of time) or only for a short time.
"The requirements for SMN might change" over time, Monani said. "You might be able to allow levels of the protein to drop at some point without adversely affecting the person."
"Things are looking very bright for the SMA community," Monani said. "Compared to some areas, the SMA field has moved much further along."
For more about experimental treatments in development for SMA, many with MDA support, see