Squeaking by on December 23rd as the last new drug approval of 2016, Biogen’s (Cambridge, MA) Spinraza now provides hope for the thousands of families affected by a debilitating neuromuscular disorder known as spinal muscular atrophy (SMA). SMA robs people of their ability to walk, eat, and ultimately, breathe.

In addition to Spinraza, there are 13 other new therapies making their way through the clinic, according to the patient advocacy group Cure SMA. The increase is largely due to a better understanding of the disease and a surge in funding for basic and clinical research. SMA affects about 1 in 10,000 babies born in the United States.

In this weekly, we’ll decipher the science behind SMA, explain the novel mechanism of action used by Biogen’s new drug, and find out how other drugs in development are zeroing in on this genetic disease.


Our nervous system consists of the brain, spinal cord, and a vast network of nerves that feed into every tissue of the body. Motor neurons are a type of nerve cell that sends messages from the spinal cord to muscles, enabling movement.

In order for the motor neurons to do their job, a functional protein called the survival motor neural (SMN) protein is necessary. The survival motor neuron 1 (SMN1) gene is responsible for producing most of the SMN protein used by the body. A second, closely related gene is the survival motor neuron 2 (SMN2) gene, which produces a much smaller amount of SMN protein and is seen as a sort of “back-up” version to SMN1.

SMA is caused by a variety of mutations in the SMN1 gene. Without functional SMN protein, the neurons do not work correctly and eventually die. How soon they die depends on the extent of the SMN deficiency, which correlates with the severity of the disease: the less SMN produced, the more severe the disease.

The back-up gene, SMN2, produces a small amount of functional SMN protein. However, differences in the way SMN2 functions means most (but not all) of the protein is non-functional and degrades shortly after being produced. Patients with less severe forms of the disease usually have extra SMN2 copies because ultimately, even tiny amounts of SMN protein provides some motor nerve function.

The four generally accepted classifications of SMA are:

Type 1: The most severe and the most common. Babies do not move, but lay perfectly still in their cribs. As the disease progresses, toddlers have trouble with swallowing and respiratory function. SMA Type 1 is usually fatal by age two.

Type 2: Symptoms manifest between six and eighteen months. These children can typically sit but not stand or walk. Respiratory function is often compromised, however with the help of machines many of these patients live into adulthood.

Type 3: Symptoms occur after age one. These kids are usually able to walk, but may lose that ability as the disease progresses. Respiratory function is less impaired, and life expectancy is often near normal.

Type 4: This is the adult-onset form, typically developing at age 30 or later. Muscles gradually weaken, and the patient often needs to use a wheelchair later in life. Life expectancy is not affected.

SMA Type 1 is the most common and most severe, making up 60% of cases. As a result, many companies are looking to tackle this segment of the disease population. Below find a few treatment approaches for SMA Type 1.


Developed by Biogen in partnership with Ionis Pharmaceuticals (Carlsbad, CA), Spinraza is one of a small but growing class of drugs: antisense therapeutics. It is a synthetic mRNA molecule that binds to the naturally occurring SMN2 mRNA in such a way that more of the mRNA is used to make the protein. The result is greater amounts of full-length, functional SMN protein. Recall from high school biology that mRNA provides the instructions to make proteins. If the mRNA is working properly, the correct, functional protein is made.


PTC Therapeutics (South Plainfield, NJ) — in partnership with Roche (Basel, Switzerland) — has begun Phase II clinical studies on its proprietary small molecule drug, RG67800. RG67800 is similar to Spinraza in that it changes the way nerve cells process the SMN2 mRNA, resulting in increased production of functional SMN protein. However, a notable difference is the delivery mechanism—Spinraza is an injectable while RG67800 is a pill. Novartis (Basel, Switzerland) is preparing for Phase I clinical testing of a small molecule modulator of SMN2 mRNA.


As a single gene disorder, SMA is an ideal candidate for a gene therapy approach. Scientists deliver the corrected version of the mutated gene by a viral vector — a virus that has been stripped of its disease-causing ability, and modified to carry a correct version of the mutated gene. The viral vector can also be engineered to drop its genetic cargo into specific cells. In the case of SMA Type 1, the AAV9 vector crosses the blood-brain barrier and delivers corrected copies of the SMN1 gene into motor neuron cells in the brain.

AveXis (Bannockburn, IL) has a gene therapy candidate, AVXS-101, in Phase I/II clinical studies. The company reported promising results in mid-2016, noting that the drug appears to be safe and effective. Babies who received this gene therapy showed marked increases in SMN production and in movement. Also in the gene therapy mix is Voyager Therapeutics (Cambridge, MA) with their treatment currently in preclinical development.

With additional approvals hopefully to follow in the wake of Spinraza, SMA patients and their family members are hoping to kiss this devastating illness goodbye.

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