Research

The research picture has brightened considerably in the last decade for people with chromosome 5-related spinal muscular atrophy types 1 through 4, thanks to special genetic circumstances that provide researchers with unique opportunities for intervention.

Since 1995, scientists have known that a deficiency of functional SMN protein is the underlying cause of chromosome 5 SMA. (SMN stands for survival of motor neuron.)

Two nearly identical genes carry the genetic instructions for the SMN protein: SMN1 and SMN2. Proteins made from the SMN1 gene are full-length and functional, and appear to be necessary for the survival and proper function of the motor neurons. By contrast, proteins made using instructions from the SMN2 gene are shorter and tend to be less stable.

In SMA types 1 through 4, flaws (mutations) in each of the two copies of the SMN1 genes result in insufficient production of full-length, functional SMN protein.

Fortunately, a certain amount of full-length SMN protein can be made from the SMN2 gene. Many people have multiple copies of the SMN2 gene. These extra SMN2 genes can lessen the impact of a flaw in both SMN1 genes. In chromosome 5-related SMA, the more SMN2 genes a person has, the milder the course of SMA is likely to be.

Researchers are seeking to exploit this unique redundancy through development of various strategies that restore sufficient levels of the needed full-length SMN protein.

Here is a look at some of the leading research strategies currently being tried in different forms of SMA.

Raising SMN levels through gene therapy
Raising SMN levels without gene therapy
Stem cells
Newborn screening

Targeting muscle
X-linked SMA research
Chromosome 14-related (DYNC1H1) research


Raising SMN levels through gene therapy

One research strategy to treat chromosome 5-related SMA types 1 through 4 is based on transferring SMN1 genes into the body to raise the level of full-length SMN protein. It has not yet been tested in humans, but laboratory experiments have been encouraging.

In a 2010 U.S. experiment, very young mice with an SMA-like disease received intravenous injections of genes containing instructions for the SMN protein, packaged inside modified type 9 adeno-associated viruses (AAV9 vehicles). The AAV9 vehicle reached its target — motor neurons in the spinal cord — and increased levels of SMN protein were subsequently found in the animals' brains, spinal cords and muscles. The mice showed dramatic improvement of motor function and brain-to-muscle signaling, and a significant increase in survival. (This same gene delivery method later was successfully used in a monkey, although the monkey didn't have an SMA-like disease and SMN genes weren’t involved.)

Also in 2010, a British research group transferred SMN genes inside AAV9 delivery vehicles intravenously into mice with an SMA-like disease, improving the life span in these mice.

Brian Kaspar at Nationwide Children's Hospital in Columbus, Ohio, discusses gene transfer in SMA in a May 2010 podcast.

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Raising SMN levels without inserting new genes

Several research strategies involve manipulating the genetic instructions provided by the SMN2 gene so that more full-length SMN protein can be made.

With MDA support, a company called Repligen has developed an experimental compound called RG3039, which is designed to interfere with an enzyme and thereby increase production of full-length SMN protein from the SMN2 gene.

Another strategy in development for SMA is using antisense oligonucleotides to cause more full-length SMN production from SMN2 genes. In 2010, MDA-supported scientists announced that mice with an SMA-like condition showed a "robust and long-lasting increase" in full-length SMN protein in their spinal cords and in the motor neurons themselves after experimental antisense treatment.

Antisense for SMA continues to show promise. A February 2012 podcast features researcher Arthur Burghes discussing this strategy.

Illustration of SMN1 and SMN2 in SMA
Genetic information moves from its storage form as DNA to a set of instructions known as RNA, from which protein molecules are made. Most of the RNA instructions from the SMN1 gene tell the cell to make full-length SMN protein. Most of the instructions from the SMN2 gene tell the cell to make short SMN protein.

Another strategy being explored for SMA is prolonging the life of the shortened SMN protein molecules made from SMN2 genes. Researchers announced in 2010 that the shorter SMN protein produced from SMN2 is still functional but subject to rapid destruction in cells because it has a molecular "degradation" signal. They said their findings suggest it may be possible to interfere with this molecular "trash me" tag and increase the stability of the SMN2-derived protein.

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Stem cells

Stem cells are cells that are early in their development and can give rise to specialized cells as they mature, or differentiate. Stem cells can be retrieved from embryos and fetuses, but they also have been found in the tissues of adults and children. One use of stem cells is to recapture a disease process "in a dish," by comparing the differentiation of stem cells with and without an SMA-causing mutation.

Another application of stem cell research in SMA is the possibility of transplanting stem cells at various stages of differentiation (maturation) into people with the disease, with the expectation that they will either become the needed motor neurons themselves and/or will secrete substances that will help sustain existing motor neurons.

California Stem Cell is particularly interested in this strategy. In December 2010, this biotechnology company filed an application to begin testing a stem-cell-based strategy in SMA.

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Targeting muscle

In 2012, an MDA-supported research team reported that a drug called fasudil, which is only approved for research use in the United States, extended the average life span of mice with an SMA-like disease from approximately 30 days to more than 300 days. The researchers believe the drug targeted muscle, not nerve cells, opening another possible therapeutic avenue for SMA.

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Newborn screening

Most evidence suggests that treatment of babies with type 1 SMA should be done as early in life as possible, and that it may be necessary to start screening for the disease in newborns to identify them early.

In May 2011, the U.S. National Institutes of Health announced it would fund a pilot study of newborn screening to identify babies destined to develop SMA.

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X-linked SMA research

An X chromosome gene has been identified that, when mutated, causes X-linked SMA. The gene codes for the UBE1 protein, which is part of a cellular waste disposal system. Without functional UBE1 protein, this important waste disposal system probably malfunctions.

Scientists are now studying the UBE1 gene and protein with an eye to identifying therapeutic targets in X-linked SMA.

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Chromosome 14-related (DYNC1H1) research

Flaws in the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene on chromosome 14 can lead to a rare form of SMA called SMA-LED, which predominantly affects muscles in the legs. The DYNC1H1 gene works as a "motor" to transport cellular components. Mutations in the DYNC1H1 gene result in disruptions to the motor's function. Much work is yet to be done on this newly discovered cause of SMA.


For an in-depth discussion of several research strategies in SMA, read SMA: Full Speed Ahead, and see the SMA Research section from the Quest series In Focus: Spinal Muscular Atrophy.

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