Adrian Krainer, PhD, with his 2021 Wolf Prize in Medicine at New York’s Cold Spring Harbor Laboratory. Credit: Larry Luxner

COLD SPRING HARBOR, New York—Five years after the approval of Biogen’s nusinersen (Spinraza®) to treat spinal muscular atrophy (SMA), more than 11,000 people worldwide receive the lifesaving drug regularly.

“That’s like a dream for a basic researcher,” said Adrian Krainer, PhD, the scientist who perfected the RNA splicing technique that eventually led to the development of nusinersen—which won the blessing of the US Food and Drug Administration (FDA) on December 23, 2016, as the first-ever therapy to treat this rare neuromuscular disease.

Dr. Krainer spoke with Rare Disease Advisor from his office at Long Island’s Cold Spring Harbor Laboratory (CSHL), where he’s been a researcher since 1989. He’s also deputy director of research at CSHL’s Cancer Center division.   

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“I’ve been studying RNA, and RNA splicing in particular, since I was a graduate student,” he said. “Over the course of this research, I came to realize how important splicing can be in the context of genetic disorders and cancer.”

Born and raised in Montevideo, Uruguay, and the son of Jewish Holocaust survivors, he won a scholarship in 1977 to study biochemistry at New York’s Columbia University. In 1986, he earned a PhD in biochemistry from Harvard University in Cambridge, Massachusetts.

“If I had stayed in Uruguay, I would have gone to medical school, and medicine was not my calling,” said Dr. Krainer, 63. “I understood that if I wanted to do research in genetics, the top place to be was the United States.”

After graduation, he ended up at CSHL, a private nonprofit research institution that employs 1500 people in 60 labs. The facility, which excels in molecular biology, receives 12,000 visitors a year and has produced 7 Nobel laureates since its founding in 1890.

“Before nusinersen, there was no real treatment for SMA. People were just trying to alleviate the suffering, for instance, difficulty breathing, by using ventilators,” Dr. Krainer said. “There was some physical therapy, but basically, very little could be done. The need for therapy was acute.”

More than 90% of spinal muscular atrophy patients have defects of the survival motor neuron 1, or SMN1, gene. Typically, patients with SMA have a homozygous deletion of exon 7 in SMN1. While survival motor neuron 2 (SMN2) is a nearly identical copy of SMN1, it doesn’t compensate for the loss of SMN1 due to predominant skipping of exon 7—a loss that can be corrected with SMN2 splicing.

Dr. Krainer began working on SMA in 2000, the year after the publication of a paper describing how SMN1 and SMN2 genes are spliced.

“SMA patients don’t have a functional SMN1 gene, so they depend on SMN2. But because of the splicing nature of SMN2, it makes only a small amount of functional protein. The first couple of years, we studied the difference between SMN1 and SMN2, given there are very few nucleotide differences between them,” he explained. “That very basic work gave us some understanding and led us to start thinking about what can we do now to increase exon 7 inclusion in the RNA of SMN2. And then we started very seriously screening for antisense oligonucleotides to do that.”

The entrance to Cold Spring Harbor Laboratory on New York’s Long Island. Credit: Larry Luxner

In 2004, Dr. Krainer’s lab began collaborating with Ionis Pharmaceuticals. Four years later, he published the sequence of nusinersen.

“We showed its effectiveness in a mouse model,” he said. “We worked in cell‑free systems, cell lines, patient‑derived fibroblasts, and then mouse models of SMA as they were becoming available. That’s what we consider preclinical development. It was about 8 years of work. In November 2011, the Phase 1 clinical trial started.”

The National Institutes of Health along with the Muscular Dystrophy Association (MDA) helped fund Dr. Krainer’s work as he and Ionis moved into mouse models. In June 2018, Biogen paid Ionis $1 billion for the rights to develop, manufacture, and commercialize nusinersen.

“We were very grateful to the MDA because the mouse studies were really critical to show that this idea would work in vivo,” he said. “The results were very striking in that we could extend the survival of mice with severe type 1 SMA. They were running around fairly normally. It was a very important preclinical stage of the work to then justify clinical development.”

For his achievements, Dr. Krainer won Israel’s 2021 Wolf Prize in Medicine. The $100,000 award is considered one of the most prestigious achievements in medicine, after the Nobel Prize.

“We have seen some incredibly striking results. Most strikingly, if you treat very young SMA patients who have the genetic diagnosis—but before the onset of symptoms—you can basically prevent the onset of the disease,” he said. “So far, that’s been the case for up to 5 years, and we hope it will be the case forever. What more can you ask for?”

A poster honors all those who worked at Dr. Adrian Krainer’s lab at Cold Spring Harbor Laboratory between 2008 and 2016, during the development of nusinersen. Credit: Larry Luxner

Since the FDA’s approval of nusinersen, 2 more SMA therapies have come on the market: the Novartis one-time gene therapy onasemnogene abeparvovec-xioi (Zolgensma®) and Roche’s risdiplam (Evrysdi®), a liquid taken once a day by mouth or feeding tube.

Asked how nusinersen stacks up against its 2 rivals, Dr. Krainer said he’d be reluctant to draw any conclusions at this point.

“I don’t think anybody has a sound basis to compare efficacy, because you would have to do head‑to‑head comparisons and a clinical trial, and I’m not aware of those being done,” he said. “There are some clinical trials underway in which patients switch from one treatment to another. All 3 therapies aim to increase the levels of SMN protein, which is the basis of the disorder in that the SMN levels are lower than they should be.”

These days, Dr. Krainer spends his time researching such diseases as familial dysautonomia, cystic fibrosis, pancreatic cancer, liver cancer, and pediatric brain cancer. He remains on the board of Cure SMA and is a strong proponent of newborn screening for SMA.

“This is extremely important, because then you can catch these cases when the intervention can be done right away,” he said. “That’s when it helps the most.”