It’s a devastating image: an infant held in a physician’s outstretched hand, her limbs drooping weakly in places where the hand offers no support. Unfortunately, this image is witnessed by thousands of parents in the United States each year as doctors diagnose their new bundle of joy with the devastating disease of Spinal Muscular Atrophy (SMA). As a pediatric neurodegenerative disease, SMA is the leading genetic cause of infantile death, as well as the leading genetic killer of children under the age of two. Occurring once in every six thousand live births, SMA affects children of all races, ethnicities, and economic backgrounds.
An associate professor in MU’s Department of Veterinary Pathobiology, Christian Lorson has dedicated his life’s research to understanding the cause of SMA in hopes of someday developing therapies to replace the diseased gene with a ‘healthy” gene.
Lorson, who teaches classes on virology and molecular biology in both the School of Veterinary Medicine and the School of Medicine at MU, explains that there are three distinct types of SMA, marking differences in the age at onset and in the severity. While the symptoms of SMA are broad, all types involve some degree of loss of function in the voluntary muscle groups. The majority of deaths caused by SMA are not related to diminished muscle activity, however; they are caused by respiratory complications due to infections.
Individuals with type one SMA, the most severe form of the disease, experience a very rapid loss of muscle activity within the first few months of birth, with physicians sometimes referring to them to as “floppy babies.” Like the image evoked by the term, these babies are unable to support the weight of their own body parts and often die within two years of birth. Individuals with type two SMA are affected by the same symptoms slightly later in life. These children may be able to reach such early milestones as learning to sit, but they may never be able to stand because of the onset of muscle activity loss and often die during childhood.
In type three individuals, the onset of symptoms is significantly delayed, often into adolescence. These children may be able to reach a number of developmental milestones, such as sitting, standing, and talking, but when the symptoms of the disease manifest themselves the children frequently are confined to wheelchairs from that point on. In ten percent of new SMA cases, individuals have normal lifespans, although they may be limited to a wheelchair for much of their lives due to the muscle loss caused by the disease.
Although Lorson and his research team have made significant progress in their research, there are still a lot of unanswered questions. “We know what the disease is caused by; it’s the loss of this specific gene Survival Motor Neuron (SMN). But we don’t understand why it causes SMA,” he says. While several theories have been proposed, Lorson believes the key lies in discovering what the SMN protein does in a motor neuron, or the mechanism responsible for making muscles move in the human body. “That’s a very basic biological question, but it also impacts how you treat the disease and how you begin to develop therapeutics,” he adds.
Lorson and his team have developed a gene therapy program. “We are trying to replace the gene,” he explains in describing the process. “We use a viral vector to deliver short molecules that can then go in and correct a similar genenot the actual SMA disease-causing gene but a very closely related back-up copy.” You might wonder why Lorson would focus on replacing only the ‘back-up’ copy of the SMA gene instead of replacing the actual disease-causing gene itself. “The disease-causing gene is called SMN-1 and the back-up copy is called SMN-2,” he notes, “so if we can redirect the gene expression of the back-up copy, that should allow us to achieve normal levels of SMN, and then you have full functional protein activity.” In short, if the back-up gene is activated, the hormone levels will change enough that the actual disease-causing gene behaves normally.
While he uses anonymous samples from tissue banks to conduct research in the lab, Lorson says that he and his staff benefit immensely by interacting with children and the families of children actually impacted by SMA: “I think it provides a sense of urgency. When you talk to family members who are affected by this, you remember that it’s not some abstract pie in the sky. This is something that affects them every single minute of every single day. It’s all-consuming.” Lorson brought his lab team to the Kansas City area to visit friends who have two children diagnosed with SMA. “It’s really nice to see the rest of the lab get involved, playing wheelchair soccer or wheelchair Frisbee,” he reflects. “They are opportunities to really own your project and understand how you can directly impact the science and, by extension, someone’s life.”
Clinical trials are about to begin that involve SMA-specific compounds. This is really the first opportunity to put new discoveries to the test to see whether they will be successful in treating SMA. Looking forward, Lorson has a lot of goals for his research: “I’d love to see us helping to establish some clinical trials and actually push either drugs or RNA oligonucleotides to the forefront.” He says the next step is to apply this work to animal models in order to prove efficacy, showing that SMA gene expression can be turned around.
In addition to his research on SMA, Lorson is also associated with an organization based in Richmond, Virginia, called Fight SMA. “It is a patient advocacy group designed not only to raise awareness but also to raise funds for research,” he says. Some of the proceeds have been used to fund Lorson’s research. “This is money that was raised through garage sales or through golf events, and it came from moms and dads who have an ill child, so it really is a big deal when you take this money. You have an obligation,” he emphasizes. He explains that this money is more often than not directed primarily at developing therapies for a cure.
Other funding sources, such as the grant from the University of Missouri Research Board, help underwrite Lorson’s basic research into the cause of SMA. In fact, the Research Board support proved particularly timely and crucial. As he puts it, "the UMRB grant allowed us to establish ourselves in new areas. With this support, we were able to win two large NIH awards, which are now the foundation of our lab."
Great progress has been made in the study of SMA, thanks in part to Lorson’s research. “If you were to go back in time, about twenty years ago, physicians would tell parents to take the children home, love them, and enjoy the remaining time with them,” he recalls. “But there have now been enough inroads into supportive care that for many individuals that they can have a significantly extended life span.”