The case of Spinal Muscular Atrophy: Deadly inherited diseases start to yield

Part 1

A few years ago, a friend asked me if I could take over a basic science lecture he was scheduled to give to 220 first-year medical and dental students at Columbia’s Vagelos College of Physicians and Surgeons. He had to go to a wedding or take a kid to college or some such. He handed me his PowerPoint presentation, grinned and said, “Good luck.” I had two weeks to work on it.

The lecture was on how genes are turned on and off, and I had started my career when that was known only in bacteria. I had the advantage of watching the subject develop toward clinical utility over nearly 50 years. The students had not yet tumbled to the fact that the lecture was being taped and they could watch it in their pajamas the next day, so they were all there. I decided to start with bacteria way back when, move to the surprise that had occurred in gene regulation and then tackle a serious disease. It was teaching heaven and I had three hours.

At the time, researchers in our department and in other universities were working on an inherited disease called Spinal Muscular Atrophy (SMA), the most common genetic disease of childhood, after cystic fibrosis. It is as dreadful as it sounds. Newborns with SMA lose muscle tone, become floppy and are unable to sit up or move. As the most severe form of the disease progresses, breathing becomes impossible. The reason is that the child’s motor neurons fail. These nerve cells originate in the spinal cord and extend processes called axons to control skeletal muscles. When they fail, affected children can’t breathe and usually die before the age of two. In three milder forms of SMA, patients can live into their teenage years.  

What has gone wrong in SMA patients? 

We have about 3.2 billion units of DNA in our genomes, the familiar A, C, T and G, which stand for chemical structures called nucleotides. The nucleotides are strung together to form 23 chromosomes. We have two copies of each chromosome and if the SMA gene in both is mutated, the patient will likely develop the disease. It is a peculiar type of mutation and we understand it well from a molecular point of view and that has enabled researchers to develop treatments. Five or six years ago, these were limited to mice with SMA. In the human population, there is one SMA case per 11,000 births, which means that one in 50 of us is a carrier.  There was no treatment. But now there is.

The defective gene of this motor neuron disease provides the code for a protein called SMN1, for Survival of Motor Neurons. To survive in the body, neurons need a variety of protein factors to keep them going and SMN1 is one of them. The SMN1 gene has been studied relentlessly — its sequence of A, T, G and Cs is known, and basic researchers discovered that a small but crucial part of the protein, called an intron, produced from the DNA instructions has been left out. 

The DNA of the normal gene has been isolated and the goal became to find a way to introduce the normal gene into a patient’s neurons and have it make the normal SMN1 survival factor. Such research always starts with mice since experimenting with humans is both difficult and morally fraught. My colleagues and others bred mice in which the SMA equivalent gene was mutated and their offspring showed the same muscle deterioration as affected children. 

There are many reasons that correcting neurological defects like SMA has been hard, but let’s start with biology. With a few exceptions, nerve cells in the brain or spinal cord do not divide after birth. Neurons live in their own architecture and we have to treat them where they lie. In addition, other cells surround neurons to form a barrier, so to be effective, a drug or a corrective piece of DNA traveling in a blood vessel must cross two cell layers that have evolved to keep noxious agents out. Getting therapies past the so-called blood-brain barrier is no easy trick. 

Astonishingly, there are now several ways to treat newborns with SMA, all derived from basic research. While there is no complete cure, there is hard won progress in this and other genetic diseases. The two treatments for SMA and something about the students and researchers who do this work will appear in the next column.


Richard Kessin is Professor Emeritus of Pathology and Cell Biology at Columbia University. He lives in Norfolk. Reach him at Richard.Kessin@gmail.com.