What is Spinal Muscular Atrophy (SMA)? SMA is a devastating neuromuscular disease that robs people, usually babies and young children, of the ability to move. This includes all voluntary muscles in the arms, legs, hands, the muscles in the back that allow us to sit upright, the muscles in the neck that allow us to hold our heads up, the muscles that allow us to swallow food or saliva, and even the muscles needed for breathing.

There are four types of SMA:
1. Type I is the most common and most severe form is usually diagnosed before six months of age. These infants never sit without support or crawl and due to profound respiratory weakness and difficulty swallowing these infants have a limited lifespan. Without intensive medical intervention 50% of infants with SMA I die before the age of 1 and 90% die before the age of 2.
2. Type II is the second most common form of SMA and is usually diagnosed between the ages of 6 months to two years. Children with SMA type 2 can usually sit up and crawl but never walk. Many survive to adulthood but often have a shortened lifespan.
3. Type III is much less severe and is usually diagnosed between 18 months and 3 years old, but it can be diagnosed much later. People with SMA Type III are able to walk but may require a wheelchair as the disease progresses. They usually have a normal lifespan.
4. Type IV is uncommon, onset is during adulthood often after age 35 and the symptoms are much less severe.

All types of SMA are progressive, muscle weakness will worsen over time. In Type I this can lead to complete paralysis with the only voluntary movement that remains is the ability to blink the eyes.
What causes SMA? SMA is a genetic condition caused by a mutation in just one of our 30,000 genes. This gene, Survival of Motor Neurons 1 (SMN1), is expressed in every cell of every animal on the planet. Mutations in SMN1 are recessive, which means that if we inherit only one copy of mutated SMN1 from one of our parents, but not both, we will probably never even know it exists. But, if both parents are carriers of mutated SMN1 (1 out of 40 people are carriers) then any of their children have a 25% chance of inheriting two copies of the mutated SMN1.

Nearly everyone born with two copies of mutated SMN1 will develop SMA. Although every animal on earth has the SMN1 gene, only humans are able to develop SMA. This is because humans have a near duplicate copy of SMN1 called SMN2. The SMN 2 gene is able to produce the critical SMN protein exactly like the protein produced by the non-mutated SMN1 gene, except that there is a single change in the letters of the DNA of the SMN2 gene that affects a process called splicing of this genes messenger RNA (a temporary copy of the genes DNA sequence that is the template for protein production). When SMN2 RNA is improperly spliced 90% of the protein it produces is too short and unable to function properly. This leads to a reduced amount of SMN protein in cells.

Too little SMN protein in the critically important cells that transfer the messages for movement from the brain to the muscles, motor neurons, too little SMN protein causes is deadly. Once motor neurons die muscles no longer get the signals to move and they weaken and atrophy just like the muscles of someone lying in bed and never moving would do. The SMN2 gene can be present in different numbers of copies from one to four or more. Usually, the more SMN2 genes there are in a person’s cells the more SMN protein can be produced, and the less severe the symptoms of SMA usually are. Although the correlation between type and SMN2 copy number is not 100% people with SMA Type 1 usually have 2 copies of SMN2, People with Type 2 usually have 3 copies, and people with Type 3 most often have four copies of SMN2.

How is SMA diagnosed?
SMA is the most common “rare” genetic disease. One out of every forty people in the world carry the mutated SMN1 gene. And 1/6000 babies are born with the disease every year. Doctors experienced with SMA can suspect it based on symptoms and physical examination. But a DNA test must be conducted to detect the mutations in the SMN1 gene that confirm this diagnosis. At the same time a test to determine SMN2 gene copy number can also be done. This information can be helpful in trying to predict the severity of SMA symptoms a person will have, but there are other mutations and other genes that can also modify the course of the disease so SMN2 copy number does not accurately predict the course of the disease for all people.

What are the prospects for people diagnosed with SMA? There are four words that ring in the ears of everyone who hears the diagnosis of SMA: “No cure. No treatment.” But today there is more hope than ever for people coping with this disease! There are a number of innovations in respiratory, nutritional, and supportive care for people with SMA. These innovations can improve the health, lifespan, and quality of life of people with SMA so much so that they are changing the life history of people born with SMA Type 1
Also, since the discovery of the SMN1 gene and the back-up gene SMN2 in the mid 90’s there has been a surge in research on the disease and in approaches for treatment of the disease. There are so many promising approaches to treating SMA under development right now that the National Institutes of Neurological Diseases and Strokes (NINDS) ranks SMA as the neurological disease that is closest to a treatment or cure!

This is the new graphic illustrating the SMA drug pipeline from, formerly Families of SMA, showing many of the treatment approaches and their general mode of action.

SMA pipeline

Each of these treatments works differently. ISIS/Biogen/ASO is an approach that uses a synthetic molecule similar to a very short piece of DNA or RNA. This molecule binds to the RNA from the SMN2 gene and corrects its aberrant splicing so that a full length SMN protein can be produced. The drug is injected in the cerebro-spinal fluid through a lumbar puncture similar to the way an epidural is administered to women in labor. This approach addresses SMN protein depletion in the Central Nervous System but is not likely to affect peripheral systems like the liver, kidneys, heart, and other tissues where increased SMN protein may provide benefit. The Morpholino ASO approach at Ohio State University is essentially the same but uses a different chemistry in the synthetic RNA molecule (ASO). These approaches seem to have the potential to correct SMN2 splicing from 10% full length, to 90% full length in tissues where they are delivered.

Pfizer/Quinazoline is a small molecule (drug) that blocks an enzyme called DcpS. This enzyme is involved in the recycling of used RNA molecules. By blocking its activity the SMN2 RNAs half-life is extended making it available for use as a template for SMN protein synthesis for a longer period of time and leads to increased SMN protein production.

Roche/PTC is another small molecule but it acts similar to the ISIS and Morpholino ASOs by correcting the splicing defect in SMN2 RNA. An important distinction about this molecule vs. the ASOs is that it can be taken orally and it is able to penetrate the blood brain barrier so that it can affect SMN2 splicing in both the central nervous system and peripheral systems.

Paratek/Tetracycline and NINDS/Indoprofen are small molecules that act on the SMN2 RNA in a different way. Part of the reason mis-spliced SMN2 RNA produces a truncated (too short) SMN protein which is non-functional, is that when SMN2 is aberrantly spliced it introduces a signal to stop making protein into the RNA template. These drugs cause the protein making machinery to ignore this signal and continue making a longer protein. The extra portion is not the correct SMN protein but it does help stabilize the protein so that it is available to produce biological effects for a longer period of time.

Novartis, CALIBR, Indiana U, and Harvard are early small molecule approaches that either attempt to increase the activity of the SMN2 gene, correct the splicing of the SMN2 RNA, or extend the lifespan of the SMN protein or more than one of these approaches.

AveXxis and Genzyme are both developing gene therapy approaches in which a harmless virus is genetically modified to express the missing SMN1 gene. This virus is unique in that it can be injected intravenously and still penetrate the blood brain barrier and enter into the critical motor neuron cells. In addition to entering motor neurons and other cells in the central nervous system the virus can enter into other tissues such as the liver, heart, kidneys, etc. This is a very promising approach that has produced stunning results in the survival of the mouse model of SMA type 1, giving them a nearly normal lifespan.

Trophos/Olesoxime is a small molecule that instead of trying to affect SMN protein production acts as a neuro-protectant. This molecule can enter the central nervous system and peripheral tissues and it is hoped that it will help to prevent the death of motor neurons due to depletion of SMN protein. This drug seems to have stopped progression of the disease in SMA Type 2 and 3 people in a large phase 3 clinical trial and may be the first drug to be approved for treatment of SMA.

Cytokinetics/Tirasemtiv is a small molecule that, like olesoxime, does not try to alter SMN protein production but acts at the level of the muscle cells. This molecule makes muscle cells more sensitive to signals from nerves cells. So, in SMA where nerve cells and their connections to muscle fibers are reduced, it is hoped that this molecule will sensitize muscle cells so that they are able to contract even when they are given a weaker signal from the motor neurons.

Besides the fact that there are so many potential treatments under development, it is important to also note that there are many different ways these potential treatments target the disease. This is important for two reasons. First, if one approach to treating the disease hits a dead-end, there are other approaches that still have the potential to work. Second, the fact that different treatments target the disease in different ways means that if two or more treatments work alone, it may be possible to combine treatments and achieve even better results than any single treatment can alone. A combination such as ASOs to correct SMN2 splicing plus, quinazoline to extend the half-life of SMN2 RNA, plus Olesoxime to protect neurons from damage, plus Tirasemtiv to make muscles respond to reduced nerve impulses, any of the other combinations may provide a route to a more productive treatment for SMA. Also, some people may not respond to certain treatments and therefore need alternatives. 10% of people have antibodies to the virus used in gene therapy so they will probably not be able to benefit from this treatment. Another treatment or combination of treatments may be their best option.

What does the future hold for People with SMA? Although this is the most exciting and hopeful time since the fateful SMN mutation arose in the human genome 5 million years ago, it is also a very frustrating time for people with SMA and their families. Such promising treatments seem to be almost within our grasp! But none are widely available today.

Even though researchers are justifiably excited about their recent progress, families remain stymied by lack of access to treatments outside of clinical trials that are very limited in size and restricted by age, type of SMA, and physical condition. The first treatment to delay or halt the progression of SMA may be available within as little as a year but the most promising treatments that have the possibility of improving, or even restoring motor function are not likely to be widely available for several years.

Recently we have come so far so fast in treating this scourge that has haunted our kind since long before we and Neanderthals became separate species. Perhaps the greatest comfort we may take is in knowing that we may soon be faced with the quandary of choosing between multiple treatments and combinations of treatments for this disease.

For more scientific discussion on SMA, please visit our related blog,