黑料吃瓜资源

Another proof of principle for TSUNAMI method in modeling spinal muscular atrophy and other splicing-related illnesses

Cold Spring Harbor, NY — A research team at 黑料吃瓜资源 (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 Ionis 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 genetic cause of childhood mortality. 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鈥檚 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 鈥淪MN鈥� stands for 鈥渟urvival of motor neuron鈥� and suggests why SMA is so serious.聽The SMN1 gene encodes a protein, called SMN, that motor neurons 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鈥檚 manufacture of the SMN protein from the SMN2 gene can limit the impact of SMA.聽 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.聽 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鈥檛 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 鈥渕essage鈥� is edited incorrectly, in a process called pre-mRNA splicing. The flaw in the protein鈥檚 production is understood. 鈥淲hat we don鈥檛 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,鈥� Krainer explains. 鈥淭hat鈥檚 why we set out to create a model in the adult mouse.鈥�

The Krainer lab鈥檚 TSUNAMI technology actually intensifies SMA鈥檚 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鈥檚 lifespan.

鈥淥ur efforts to model the adult form of SMA were successful,鈥� says Kentaro Sahashi, M.D., Ph.D., a postdoctoral researcher and neurologist who is first author of the team鈥檚 new paper.聽鈥淲e 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鈥檚 progression in adults.鈥�

Drs. Sahashi and Krainer added: 鈥淧erhaps 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.鈥�

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

Written by: Peter Tarr, Senior Science Writer | [email protected] | 516-367-8455

Funding

The research described in this release was funded by the National Institutes of Health, the Muscular Dystrophy Association, the SMA Foundation, and the St. Giles Foundation.

Citation

鈥淧athological impact of SMN2 mis-splicing in adult SMA mice鈥� is published online ahead of print September 9, 2013 in EMBO Molecular Medicine.聽 The authors are: Kentaro Sahashi, Karen K.Y. Ling, Yimin Hua, J. Erby Wilkinson, Tomoki Nomakuchi, Frank Rigo, Gene Hung, David Xu, Ya-Ping Jiang, Richard Z. Lin, Chien-Ping Ko, C. Frank Bennett and Adrian R. Krainer. The paper can be viewed online at: .