Zolgensma’s Journey from Lab Idea to Gene Therapy for SMA

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by Grace Frank |

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How Zolgensma (onasemnogene abeparvovec-xioi), the gene therapy once known as AVXS-101, came into being is a tale fairly common to basic science: An idea that progressed from cell work in the lab to experiments with animals and, ultimately, testing as a possible treatment in patients.

Where Zolgensma’s story diverges from others, however, is in its very success.

It is now the first gene therapy approved by the U.S. Food and Drug Administration (FDA) to treat spinal muscular atrophy, a severe and genetic neuromuscular disease. Specifically, it may be given to newborns through toddlers up to age 2 with any type of SMA. Clinical trials underway aim to bring it to older patients in the months and years to come.

This gene therapy is also seen by its developers as a one-time treatment; as approved, children will be given a single intravenous administration with, they say, the potential to last a lifetime.

Zolgensma’s beginnings were relatively modest, the outcome of a conviction that there must be a way of crossing the brain-blood barrier and delivering a gene therapy to cells in the brain and spinal cord (the central nervous system).

The approach to be taken simply needed — so to say — to be an advancement on what existed toward the close of the 20th century and start of the 21st.

“I’ve really spent the majority of my career in gene therapy space,” Brian Kaspar, chief scientific officer and scientific founder of AveXis (part of Novartis since May 2018), said in a February 2018 interview about the therapy his company was then advancing in clinical tests in children.

Dr. Brian Kaspar, CSO of AveXis

Brian Kaspar, CSO of AveXis. (Photo courtesy of AveXis/Novartis)

“And the majority [of that time was spent] thinking about how do we deliver to the brain and spinal cord efficiently,” Kaspar added of his years, 2004–17, at The Ohio State University and The Research Institute at Nationwide Children’s Hospital.

Various ways of crossing the brain-blood barrier — which shields the brain from pathogens and other threats carried in the blood — were being tested, Kaspar said, including “drilling holes into the skull and dropping needles down.”

But, he added in a bit of an understatement, targeting neurons throughout the central nervous system using needles “would require many, many injections, and that just did not seem translational to us.”

Over his roughly two decades of gene therapy work, Kaspar focused on viruses as carriers.

In the mid-2000s, his lab began to screen adeno-associated viruses (AAVs) — of which “hundreds, if not thousands, of these AAV serotypes from multiple species” exist. Ongoing muscle research pointed to the likelihood that some AAVs were crossing the barrier at needed dose levels and targeting “muscle extremely efficiently.”

But several more years of work remained before a specific virus — AAV9 — would do the same in key nerve cells of the brain and spinal cord.

“Recent work in rodent models of SMA and ALS have demonstrated significant promise for gene delivery using viruses that are retrogradely transported following intramuscular injection,” Kaspar wrote as lead author of a study published in 2009 in the journal Nature Biotechnology. But “clinical development may be difficult given the numerous injections required to target … neurodegeneration throughout the spinal cord, brainstem and motor cortex to effectively treat these diseases.”

His team looked into AAVs, specifically AAV9, testing its ability to deliver a gene efficiently in these key cells in newborn and adult mice. They did, beyond the scientists’ highest hopes.

Results, they wrote, “demonstrate the unique capacity of AAV9 to efficiently target cells within the CNS [central nervous system], and in particular, widespread neuronal and motor neuron transduction in the neonate, and extensive astrocyte transduction in the adult following intravenous delivery. A simple intravenous injection of AAV9 … may be clinically relevant.”

AAV9 delivery, Kaspar said years later in our interview, skyrocketed the number of CNS cells lighting up from the few “you could count on one, no more than two, hands” to “really unprecedented levels.”

“We were shocked by the percent of motor neurons throughout the brain and spinal cord that were targeted,” he added of his and his team’s reaction. It quickly  “became clear to us that [treating] spinal muscular atrophy made sense.”

More studies followed, this time using a SMA-specific mouse model (the now widely used SMNDelta7 mouse) developed earlier by “a colleague of mine at The Ohio State University, Dr. Arthur Burghes … we had connections right next-door, literally,” Kaspar said.

A study published in 2010 in that same journal — with Kaspar again as lead author along with Burghes — concluded quite strongly. It detailed “the most robust postnatal rescue of SMA mice to date, with correction of motor function, neuromuscular electrophysiology and survival after a one-time delivery of SMN. Intravenous scAAV9 treats neurons, muscle and vascular endothelium, all of which have been proposed as target cells for treatment.”

Six of these treated mice were 250 days old when the study was “resubmitted” in November 2009, making them “some of the longest-living — if not the longest living — SMA mice, at least at the time,” Kaspar said in the interview.

Delta7 mice, he added, “typically die at 15 days of age.”

More studies in mice, pigs, and in primates followed, showing survival to degrees “never seen before,” added Sukumar Nagendran, then the company’s chief medical officer.

AveXis opened its pivotal Phase 1 trial (NCT02122952) of AVXS-101 in May 2014, testing first a low dose and then, with no unexpected safety concerns evident, a high dose in a total of 15 type 1 infants, all enrolled at Nationwide Children’s.

The rest, as they say, is history.