I recently watched a video of a young boy enjoying a ride on his bicycle. The video was sweet, and wouldn’t have been outstanding on its own, but this boy had been diagnosed with a rare, muscle-wasting condition called spinal muscular atrophy (SMA). As a research scientist, this reminded me that there is important work to be done on behalf of patients like him and their families to help overcome limitations of their disease.
The need to balance hope and practicality is important among scientists striving to help patients with rare genetic conditions. We feel for the parents, who, more often than not, notice the first symptoms when their children are very young. We’re inspired by their courage and determined to offer hope. It’s the reason we dedicate our careers to researching these conditions.
And yet, because the conditions are seen so infrequently, we must accept some basic facts: The diseases are difficult to understand, hard to diagnose, and often hard to treat.
A CHALLENGING CASE
Currently, it is estimated that between 10,000 to 25,000 people in the United States are affected by SMA, and one in 11,000 babies are born with this genetic disease.1 But these small numbers understate the urgency. SMA is the leading genetic cause of death in infants and toddlers.1 The disease impacts basic vital functions, including a person’s ability to walk, swallow and breathe.1
Researchers at Genentech and Roche are determined to better understand and develop medicines to treat diseases with high need. That process starts with advancing the understanding of the way SMA works.
SMA is caused by a mutation in a gene called “survival of motor neuron 1 (SMN1),” which produces a protein that’s found throughout all tissues in the body. Nerves that control all of our muscles depend on this protein.1 Specialized nerve cells called motor neurons transmit signals from the brain to the muscles to allow movement. Motor neurons are dependent on SMN protein for their survival and normal function. That’s why SMA-related protein deficiency causes muscle wasting that can be debilitating.
Knowing that SMN protein plays an important role in the development of SMA and is conserved across all species led our scientists to what may be an important scientific insight. We have come to believe that SMN is an essential protein for normal development and functional homeostasis—or stable equilibrium among physiological processes—not just in humans, but in all species. It’s what evolutionary biologists call a conserved pathway. This insight has led us to examine SMA in a fresh light.
BEYOND THE CNS
In the past, scientists who have studied SMA have focused on the hallmark of the condition: the progressive degeneration of motor neurons in the brain stem and spinal cord. Yet, a growing body of evidence suggests SMA isn’t only a condition of the central nervous system (CNS), but also may directly affect tissues beyond the CNS and cell types other than motor neurons.2
If SMA were just a neuronal disease affecting a neuromuscular junction, why would the body produce SMN in so many cells? Given the distribution of SMN protein throughout many tissues in the body, one could hypothesize that SMN may also play an important role in cells outside the central nervous system.
MEETING OF MINDS
We did not arrive at this understanding in a vacuum. Fortunately, others were thinking about SMA in the same way. Our partners at PTC Therapeutics laid some of the early groundwork. And we have also collaborated closely with talented colleagues at the SMA Foundation, a non-profit organization whose mission is to accelerate the development of treatments for SMA.
The process has been a true collaborative scientific exchange and our research teams have celebrated milestones on the path of hope. We also encountered setbacks. In 2016, for example, U.S. and European regulators told us that data for an investigational compound we had acquired was not sufficient for approval. We also decided to stop a second program in SMA after we had noticed development challenges we felt we could not overcome. These setbacks caused tremendous frustration for researchers and SMA families alike.
But as researchers, we recognize that stumbles are a hallmark of successful science. We refused to give up, and our setbacks ended up informing our current research path.
ON BEHALF OF FAMILIES
It’s too early to say that insights from evolutionary biology will lead us to successful treatment of SMA. That said, in animal studies, we have observed benefits in raising SMN levels in peripheral organs and tissues affected by protein deficiency. And this has defined the current direction of our clinical research. A recent review study in patients found SMA activity beyond the motor neuron, adding to evidence that SMA is a systemic disease.2 On behalf of families that struggle with SMA, we are redoubling our efforts to test our hypotheses and translate our scientific insights into programs that aim to save lives.