New Gene Therapy Drug Explained

Novartis’ (Basel, Switzerland) Zolgensma grabbed headlines last week as it garnered the second FDA approval of a gene therapy treatment for an inherited disease. Designed to treat spinal muscular atrophy (SMA), Zolgensa is also set to be the most expensive drug ever approved, with the one-time treatment ringing up at $2 million. In this WEEKLY, we’ll take explain what SMA is and how Zolgensma treats it.

SMA Primer

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 provide 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 18 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.

Zolgensma was approved to treat SMA Type 1, the most common—about 60 percent of cases—and severe form of the disease.


As a single gene disorder, SMA is an ideal candidate for a gene therapy approach because delivering a “good” copy of the mutated gene should 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.

In clinical trials, babies who received Novartis’ Zolgensma showed marked increases in SMN production and in movement—with most participants even talking and sitting without assistance. These results, combined with its status as a one-and-done cure for this devastating disease, mean that all the hype surrounding this breakthrough-designated drug just might be justified.

See You At BIO2019!

I will be giving a 75-minute talk next week on the Science Behind Immunotherapies at the BIO International Convention in Philadelphia. Please join me on June 3 at 2:30 pm, 106AB, Level 100 in in the Philadelphia Convention Center. In this talk, we’ll review the basics of how the immune system works, then explore how new treatments use patients’ immune system to fight diseases such as cancer. The talk is free for all conference access attendees.

I will also be teaching a full-day class, BioBriefing, on Sunday, June 2 during BIO2019. This class explains the science driving today’s hottest biopharma innovations, and is ideal for anyone who works on the business side of pharma without a science background. There is a cost to attend and registration is required – register today!

Interested in learning more about how drugs are priced? Join Dr. Shane Desselle for his one-day Understanding Drug Pricing class on Sunday, June 2 during BIO2019. Learn how pharmacoepidemiology influences drug reimbursement policy in the U.S. and how this affects pharmacoeconomics. There is a cost to attend and registration is required – register today!

And of course, please be sure to come visit Biotech Primer at booth 3814. Say hi, grab a T-shirt, and enter our raffle to win a pair of AirPods. See you in Philly!

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