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I've read on KEI website that in the early 2000s Dr Martine Barkats, from France, successfuly treated mice with spinal muscular atrophy (SMA) with an AAV9 viral vector; and that Dr Brian Kaspar, an AveXis executive, took it even further by treating pigs and later humans. AveXis licensed the cure for SMA under the name Zolgensma.

What did Dr Kaspar change about Dr Barkats' cure and of what significance is this change compared to Dr Barkats' work?

NOTE: Please keep the expressions and explanations as simple as possible. I am only a high school student so my biology and chemistry knowledge is limited.

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The Spinal Muscular Atrophy volume gives some historical information on the disease and its treatment in the opening sections. Their timeline and attribution of credit is rather different from that of KEI, especially where Kaspar is concerned.

Gene therapy for SMA was made possible by identifying the responsible gene in 1990 by Gilliam’s group in New York and soon after by Melki’s group in Paris. The key problem was delivery to the motor neuron. The idea that eventually became successful was suggested by Kevin Foust at the Cure SMA research meeting in Washington, DC in 2003. He was then a graduate student in Flotte’s laboratory, and he suggested testing AAV (adeno-associated virus) gene therapy using AAV2 and AAV5 genes. Later he moved to Kaspar’s laboratory at Nationwide Children’s Hospital.

In 2008, Barkats, working in Paris, and Foust at NCH discovered independently that self-complementary AAV9 gene could cross the blood–brain barrier and transduce motor neurons when injected in the bloodstream. Barkats presented the research first at the 3rd Myology Meeting. But it was Foust (working with Kaspar's group) that eventually developed the treatment for human patients. The crucial difference, however, was already present in the mice experiments, and had to do with different tagging of survival motor neurons (SMN):

"One crucial difference between the constructs is that the Barkats group in their early constructs used a tag at the 3′ end of SMN. Unfortunately, this rendered SMN nonfunctional. In Columbus, the experiments on Δ7SMA mice continued, and the collaboration among the Burghes, Kaspar, and Mark Rich (Wright State in Dayton) laboratories was born. Indeed, a remarkable effect was observed on Δ7 mice with a major increase of survival from 14 days to over a year. The function of the neuromuscular junction as well as motor unit number estimation (MUNE) and compound muscle action potential (CMAP) measures, which are used in patients, were restored."

In both original publications (below), Foust's name appears first, and Kaspar's last. According to the conventions in the field, this usually means that Foust is credited as the main discoverer, and Kaspar as the head of the lab where the discovery was made. Kaspar, now the chief scientific officer at AveXis, also managed multiple grants from National Institute of Health, National Institute of Neurological Disorders and Stroke, and various charities that funded the pre-clinical research. But he did not "discover that the AAV9 vector was capable of crossing the blood brain barrier", as KEI says. The patents for Zolgensma are owned by the University of Pennsylvania, Nationwide Children’s Hospital (NCH) and Genethon, a French charity. AveXis entered licensing agreement with Genethon in 2018, and FDA approved the treatment in May 2019.

Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes, Nat Biotechnol 27(1):59-65, 2009.

Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN, Nat Biotechnol 28(3):271-274, 2010.

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