A Story of Hope For Kids With Rare Disease

David Shaywitz

As we head into Thanksgiving, I wanted to share a story that highlights the promise and possibility that can emerge from a devastating diagnosis, and emphasizes what can happen when industry, academia, and — especially — impassioned parents and advocates join forces.

Consider the devasting rare genetic disease, spinal muscular atrophy, or SMA.

According to Cure SMA, SMA is “a progressive neurodegenerative disease that affects the motor nerve cells in the spinal cord and impacts the muscles used for activities such as breathing, eating, crawling, and walking.”  It is caused by mutations affecting the SMN1 gene, which is critical for motor neuron survival and function.

Today, there are several treatments (not quite cures) available for SMA patients, approaches that can be highly impactful in some patients, particularly if administered early in the course of the disease. 

The parents of one child with SMA have been particularly involved in driving the development of treatments: Dinakar Singh and Loren Eng, both high-powered investors whose two-year-old daughter Arya was diagnosed with SMA in 2002. The couple helped established the SMA Foundation the following year. The foundation went to work finding the most promising science in the SMA field, and ultimately securing $150 million to support basic, translational, and clinical research.

Loren Eng, president, SMA Foundation

Their drive to help their daughter was relentless.

As Loren Eng described in this piece from the Stanford Graduate School of Business magazine:

Arya had a milder form of the disease, which meant she would probably survive early childhood. But with no treatment in sight, her life would be a hellish series of hospitalizations and painful, relentless physical attrition. “The doctor said she might live to finish high school,” Eng recalls.

Eng devoted herself to changing that outcome.

As her parents and the SMA foundation fought to accelerate the development of effective medicines, Arya’s condition worsened.

By the time she was five, Arya was in a wheelchair. Each succeeding year brought new challenges as her physical capacity diminished, and the effects of her condition led to serious, sometimes life-threatening problems. As the muscles in her chest weakened, Arya lost the ability to cough, which is critical for clearing the airway during a respiratory illness. As a result, common colds could turn into pneumonia, a leading cause of death among people with SMA. “I missed tons of school because every time I got a cold, it would turn into two weeks of respiratory therapy,” Arya says.

Gradually, her muscles weakened so much that they could no longer hold bones in place. Her hips dislocated. Scoliosis twisted her spine; orthopedic deformities developed throughout her body, requiring multiple corrective surgeries. Pain shadowed her constantly.

Over time, the science advocated by the SMA Foundation advanced, and by the time she was 11, Arya was the second subject in a clinical trial for a SMA medicine. The drug candidate, nusinersen (Spinraza) is an antisense oligonucleotide aimed at the SMN2 gene, a “backup” gene that usually produces only small amounts of SMN because of alternative splicing that results in a truncated non-functional form of the protein. 

Nusinersen (developed by Carlsbad, Calif.-based Ionis Pharmaceuticals and Biogen) works by modulating splicing of SMN2 pre-mRNA, increasing the amount of full-length SMN protein that’s produced. The drug required regular injections into the spinal cord, but miraculously, seemed to halt the inexorable progression of disease in Arya. Her condition stabilized. 

Occasionally, the grueling regimen of operating-room visits and spinal injections tested Arya’s resolve. She was a little girl, and this was not how little girls were supposed to live. When she was scheduled to receive a dose on her 12th birthday, Arya broke down in tears and declared to her mother, “This is the worst birthday ever!” Eng tried to console her. “This is the best birthday present you will ever get,” she told Arya. Recalling the moment, Arya acknowledges that her mom was right. “I didn’t agree with her then, but I do now.”

She later participated in a clinical trial for a different drug, risdiplam (Evrysdi), a small molecule that also aims to increase the expression of full-length SMN2 pre-mRNA, and boost SMN production.  The mechanism of action of risdiplam (developed in a collaboration between South Plainfield, NJ-based PTC Therapeutics, the SMA Foundation, and Roche) is somewhat different than that of nusinersen. 

Most importantly, the drug can be taken as an oral pill. Arya subsequently switched to that medicine, which obviated the need for spinal cord injections. She was not eligible for a third medicine, Zolgensma (a gene therapy approach developed by Chicago-based AveXis, later acquired by Novartis), as it was approved only for much younger patients.

“Thankfully, Arya’s mind and heart have not been touched by SMA,” Dr. Chung says, adding, “She has been a strong advocate for others with disabilities.”

Now, flash forward to this summer. 

Each week, the New York Times features a wedding in their Vows section, a detailed portrait of a particularly interesting couple getting hitched. On August 9, 2024, the featured bride, who had graduated from Yale in 2022, was Arya Singh.