Intravenous AAV9 reaches the brain

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Kevin Foust, E. Nurre, C. L. Montgomery, A. Hernandez, C. M. Chan and Brian Kaspar (senior author) at the Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, with Ohio State University and Charles River. Funded by NIH (NEI R21EY018491, NINDS R21NS064328), Project A.L.S. and the Muscular Dystrophy Association. Nature Biotechnology 27:59-65, published online 21 Dec 2008 and in print January 2009. The paper's title is "Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes."

What happened

Gene therapy for brain disease normally needs surgery because most viruses cannot cross the blood-brain barrier. The team injected AAV9 carrying a green fluorescent marker (GFP) into mice. Newborn mice (day 1) received 4×10^11 particles into a vein (the text says temporal vein, the figure legend facial vein). About 56% (10 days) to 60% (21 days) of motor neurons in the lumbar spinal cord and about 64% to 71% of neurons in the Purkinje layer of the cerebellum were marked, with neurons also marked in cortex and hippocampus. Adult mice were injected in the tail vein (4×10^11 to 4×10^12 particles). There the marker appeared mainly in astrocytes (support cells): over 64% of lumbar spinal cord astrocytes, with neurons marked only in isolated spots of the hippocampus and dentate gyrus. When the same vector was injected directly into the brain, no astrocyte labelling was found (n=3), so the astrocyte result came from the vein route.

Why it moved us toward a cure

This is the starting point for brain-wide gene delivery without surgery. It led to engineered shells that reach adult neurons far better (landmark 111) and to current Parkinson's programmes that need genes to spread widely, such as GBA1 replacement (landmark 303). It also showed the limit: plain AAV9 gives little neuron delivery in adults, the age of Parkinson's patients.

Outcome

Advanced as a tool. Mouse work only; the paper itself suggested uses in spinal muscular atrophy and ALS. It was followed by Zolgensma, a one-time intravenous AAV9 gene therapy that the FDA approved on 24 May 2019 for children under 2 with SMA (Novartis release and SEC filing). Independent comment pieces appeared in the same journal (Nat Biotechnol 27:42–44 and 27:804–805); no correction or retraction is listed in Europe PMC.

Sources

• Foust et al., Nat Biotechnol 2009;27:59-65, DOI 10.1038/nbt.1515 (Europe PMC abstract; PMC2895694)
• FDA Zolgensma page (approval letters from 24 May 2019) · Novartis/AveXis release on the approval · Novartis Form 6-K, 24 May 2019
• Note: the paper shows mainly astrocytes, not neurons, in adults. Dose units are particles, not vector genomes. The Zolgensma route and vector come from search-result summaries of the Novartis release, which was not read in full.