First animal model of adult-onset SMA sheds light on disease progression, treatment

September 9, 2013

A research team at Cold Spring Harbor Laboratory (CSHL) has used a recently developed technology they call TSUNAMI to create the first animal model of the adult-onset version of spinal muscular atrophy (SMA), a devastating motor-neuron illness.

The same team, led by CSHL Professor Adrian R. Krainer, Ph.D., and including scientists from California-based Isis Pharmaceuticals, as well as the University of Southern California and Stony Brook University, succeeded a year ago in using TSUNAMI to make a mouse model of the disease as it is manifest in children. In its most severe form, called Type I SMA, the disease is the leading of . Half of infants with Type I SMA die before their second birthday.

Many SMA patients do reach adulthood, however, and on occasion people develop symptoms of the illness only after they have become adults. Hence the importance of the team's success, reported online today in EMBO Molecular Medicine.

All patients with SMA, regardless of their age, have a non-functional version of a gene called SMN1, or are missing it entirely. The acronym "SMN" stands for "survival of motor neuron" and suggests why SMA is so serious. The SMN1 gene encodes a protein, called SMN, that need in order to function. Humans have a backup copy of the gene, called SMN2, which produces the same protein, but in much lower amounts.

The body's manufacture of the SMN protein from the SMN2 gene can limit the impact of SMA. How much a patient is helped depends on the number of copies of the SMN2 gene they possess. People who have 2-3 copies (Type II SMA) make more protein and survive longer, but can never walk. Those with 3-4 copies (Type III SMA) usually have a normal lifespan and can walk early in life but accumulate various limiting disabilities over time. Type IV SMA patients have 4 or more copies of the SMN2 gene and don't experience effects of the disease until adulthood. Yet they often end up in wheelchairs.

Scientists understand why SMN2 does not efficiently yield functional protein: much of its RNA "message" is edited incorrectly, in a process called pre-mRNA splicing. The flaw in the protein's production is understood. "What we don't understand is how insufficient levels of the SMN protein in the period following development – i.e., adulthood—causes pathology in different parts of the body," Krainer explains. "That's why we set out to create a model in the adult mouse."

The Krainer lab's TSUNAMI technology actually intensifies SMA's pathological processes in mice bred to mimic the less intense forms of the illness. Thus, it can be used to recapitulate the process by which pathology manifests in different places in the body over the model animal's lifespan.

"Our efforts to model the adult form of SMA were successful," says Kentaro Sahashi, M.D., Ph.D., a postdoctoral researcher and neurologist who is first author of the team's new paper. "We observed delayed onset of motor neuron dysfunction; we noted also that SMN2 mis-splicing increases during the late stages of SMA, likely accelerating its progression in the body. We noted, importantly, marked liver and heart pathologies that were related to SMA's progression in adults."

Drs. Sahashi and Krainer added: "Perhaps most encouraging, our mouse model suggests that only moderate levels of SMN protein are needed in the adult nervous system for normal function. This means that there may be a broad time window in adult Type IV SMA patients in which to intervene therapeutically."

Dr. Krainer and colleagues, together with Isis Pharmaceuticals, have identified and characterized an antisense oligonucleotide drug that is currently in Phase 2 clinical trials.

Explore further: Low oxygen levels may decrease life-saving protein in spinal muscular atrophy

Related Stories

Low oxygen levels may decrease life-saving protein in spinal muscular atrophy

August 21, 2012
Investigators at Nationwide Children's Hospital may have discovered a biological explanation for why low levels of oxygen advance spinal muscular atrophy (SMA) symptoms and why breathing treatments help SMA patients live ...

Candidate drug provides benefit in SMA animal models

June 4, 2013
In a new publication that appears in Human Molecular Genetics, the laboratory of Christine DiDonato, PhD reports on their pharmacological characterization of the drug RG3039, demonstrating that it can extend survival and ...

Long-term correction of severe spinal muscular atrophy by antisense therapy

October 5, 2011
A new study from Cold Spring Harbor Laboratory (CSHL) reports surprising results that suggest that the devastating neuromuscular disease, spinal muscular atrophy (SMA), might not exclusively affect the motor neurons in the ...

Team introduces new method to closely model diseases caused by splicing defects

August 14, 2012
A team led by scientists at Cold Spring Harbor Laboratory (CSHL) has developed a new way of making animal models for a broad class of human genetic diseases – those with pathology caused by errors in the splicing of ...

Pregnancy hormone has unprecedented, powerful effect on spinal muscular atrophy

July 25, 2011
Researchers in Ottawa report new hope for the treatment of infants born with serious genetic disorder.

Recommended for you

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.