Stock photo of someone writing on a health record

A rare neurological disorder might not just be a disease of the nerves, researchers in the Harvard Department of Stem Cell and Regenerative Biology have found. By analyzing health insurance records, scientists in Lee Rubin’s lab have identified connections between spinal muscular atrophy (SMA) and problems in other parts of the body, including the heart and gut.

The results, published in the journal PLOS One, have implications for the diagnosis and treatment of the disease.

Using stem cells to model SMA in the lab

“SMA, for a long time, has been thought of as purely a disease of motor neurons,” said Scott Lipnick, lead author of the study. “In the 90s and early 2000s, researchers identified the gene that was underlying SMA, and they called it ‘Survival of Motor Neuron’ because they thought it was only related to motor neurons.”

Without a working copy of that gene, motor neurons deteriorate. And because motor neurons control voluntary muscle movements, patients with SMA experience muscle weakness including trouble walking and breathing.

In previous work, Lee Rubin, professor of stem cell and regenerative biology at Harvard and co-senior author of this study, made induced pluripotent stem (iPS) cells from patients with SMA.

“We used the stem cells to make motor neurons in the lab. They died really quickly, as we expected them to — but we also observed other interesting things,” Rubin said. “One thing we saw was that the stem cells generated defective heart muscle. This made us look at other defects associated with having the mutation that gives you SMA.”

Confirming the hypothesis

“This study could set the foundation for tracking the progression of SMA, so that you can tell when you might want to intervene with a therapeutic.”
Scott Lipnick

Based on their lab observations, the researchers analyzed anonymized insurance records of patients with SMA, looking for diagnoses that did not involve nerves. They found that patients also had a number of different heart and gut issues, occurring before they were diagnosed with SMA or showed major signs of neuromuscular degeneration.

“This study could set the foundation for tracking the progression of SMA, so that you can tell when you might want to intervene with a therapeutic,” Lipnick said. If heart and gut issues are noticed early in the disease progression, patients could start treatment before muscle weakness becomes severe.

Lipnick also said the study could influence how treatments are developed for SMA. Currently, the only drugs available are Biogen’s Spinraza and Novartis’s Zolgensma.

“Spinraza is delivered into the spinal cord, so theoretically it mostly only reaches the neurons in that tissue, including motor neurons, at clinically relevant doses,” he said. “Zogensma is delivered intraveneously, and it will be important to see whether it can address the SMA-related defects in tissues outside of the spinal cord.

Isaac Kohane, the Marion V. Nelson Professor of Biomedical Informatics at Harvard Medical School and co-senior author of the study, said: “There have been previous studies in mice that implicate other tissues in SMA. On top of that, genetic studies have shown that the ‘Survival of Motor Neuron’ gene is transcribed in all cells and tissues, so is likely to be important outside of the motor neuron. Our study adds patient data from a large cohort to support the notion that SMA is a systemic, multi-organ disease.”

Nerve diseases beyond SMA

“We’re thinking that this nerve-body connection is a more general phenomenon.”
Lee Rubin

This study’s main finding, that SMA is not purely a motor neuron disease, is part of a larger trend.

“SMA is one of the CNS diseases that involve peripheral tissues. There are others as well, Parkinson’s disease being the most famous,” Rubin said. “Anosmia, sleep disturbances, constipation, and other symptoms are found in patients with Parkinson’s disease. So we’re thinking that this nerve-body connection is a more general phenomenon.”

Rubin plans to take the same approach from this study and apply it to Parkinson’s disease, searching for connections among iPS cell data, medical records, and genetic sequences.

“We’d like to break Parkinson’s down into its genetic subtypes, and then ask: for each subtype, what does the whole-body picture look like?” he said. “If the cards were played properly, you could use the knowledge of the peripheral symptoms to predict the onset of the CNS symptoms, and therefore potentially treat those before they become severe.”

In this article

Photo of Lee Rubin

Lee Rubin, Ph.D.

Professor of Stem Cell and Regenerative Biology

Source article: Lipnick, S. L. et al. (2019). Systemic nature of spinal muscular atrophy revealed by studying insurance claims. PLOS ONE.

Funding: This work was supported by the SMA Foundation, National Institute of Neurological Disorders and Stroke grant P01 NS066888, the Harvard Stem Cell Institute, and the MGH Center for Assessment Technology and Continuous Health.