The Science Behind the Deal


Earlier this week, news of the $8.7 billion acquisition of gene therapy company AveXis (Bannockburn, IL) by Novartis (Basel, Switzerland) made big biotech headlines. AveXis’ lead candidate, AVXS-101, is now in Phase III clinical studies for the treatment of spinal muscular atrophy (SMA). In this Weekly, we’ll take a look at the science behind these headlines by explaining exactly what SMA is and describe the different therapeutic approaches being used to tackle this 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 neuron (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.

An orphan disease, SMA affects about 1 in 10,000 babies born in the United States. The four generally accepted classifications of SMA are:

  • Type 1: The most severe and the most common type of SMA. Symptoms are usually present within the first few months of life, and these babies often do not display movement of any kind. 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 and is a major concern, however with the help of machines many of these patients live into adulthood.
  • Type 3: Symptoms occur after age one. These patients 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 manifesting 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.

Because SMA Type 1 is the most common and severe – about 60% of cases – most of the drugs in development aim to tackle this portion of the disease population. Successful therapies will likely later be tested in the less severe forms of SMA. Below we list some approaches going after the root cause of this orphan disease—not enough SMN1 protein production.



Spinraza (Biogen; Cambridge, MA) is the only drug currently on the market to treat SMA. As an antisense drug, Spinraza is a short, synthetic piece of RNA whose sequence directs it to bind to the SMN2 mRNA (recall that mRNA is produced from a gene, and contains the information used by the cell to produce the protein specified for by the gene). The binding of Spinraza changes the way cells process the SMN2 mRNA, causing more of the information in the mRNA to be converted into protein. The end result is a greater amount of full-length, functional SMN protein.



As a single gene disorder, SMA is an ideal candidate for gene therapy approaches because delivering a “good” copy of the mutated gene could potentially cure the disease by supplying a permanent copy of the correct SMN1 protein-making instructions.

Using a “vector” — a virus stripped of its disease-causing ability — scientists are able to safely deliver corrected genes into targeted 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’ AVXS-101 has generated excitement in large part due to clinical trial observations of babies who received this gene therapy showed marked increases in SMN production and in movement – with most participant even talking and sitting without assistance. If additional studies confirm these results, the breakthrough-designated drug could be filed for FDA-approval later this year.

As a one-shot treatment, AVXS-101, if approved, offers the potential of a one-and-done cure for SMA, differentiating it from Spinraza’s three-times-a-year dosing schedule.



PTC Therapeutics (South Plainfield, NJ) — in partnership with Roche (Basel, Switzerland) — has begun Phase II clinical studies on its proprietary small molecule drug, RG67916. RG67916 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, there is a notable difference is the delivery mechanism — Spinraza is an injectable while RG67800 is a pill.

SMA is a truly devastating disease. Since its genetic basis was first discovered two decades ago, researchers have made substantial progress in understanding the disease and coming up with ways to target its molecular basis. 2018 might just be the year when that molecular understanding translates into the closest thing yet to a cure.

Share This