BackgroundNeurodevelopmental disorders, as a class of diseases, have been particularly difficult to treat even when the underlying cause(s), such as genetic alterations, are understood. What treatments do exist are generally not curative and instead seek to improve quality of life for affected individuals. The advent of gene therapy via gene replacement offers the potential for transformative therapies to slow or even stop disease progression for current patients and perhaps minimize or prevent the appearance of symptoms in future patients.Main bodyThis review focuses on adeno-associated virus (AAV) gene therapies for diseases of the central nervous system. An overview of advances in AAV vector design for therapy is provided, along with a description of current strategies to develop AAV vectors with tailored tropism. Next, progress towards treatment of neurodegenerative diseases is presented at both the pre-clinical and clinical stages, focusing on a few select diseases to highlight broad categories of therapeutic parameters. Special considerations for more challenging cases are then discussed in addition to the immunological aspects of gene therapy.ConclusionWith the promising clinical trial results that have been observed for the latest AAV gene therapies and continued pre-clinical successes, the question is no longer whether a therapy can be developed for certain neurodevelopmental disorders, but rather, how quickly.

SPTBN1 encodes βII-spectrin, the ubiquitously expressed β-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal βII-spectrin have defects in cortical organization, developmental delay, and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also present with measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals who present with developmental, language and motor delays, mild to severe intellectual disability, autistic features, seizures, behavioral and movement abnormalities, hypotonia, and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect βIIspectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain, and underscore the critical role of βII-spectrin in the central nervous system. Spectrins are ubiquitously expressed, elongated polypeptides that bind membrane lipids and ankyrins to line the plasma membrane 1,2 . The spectrin meshwork is formed by heterodimeric units of α-spectrin and β-spectrin assembled side-to-side in antiparallel fashion, which then form head-to-head tetramers that crosslink F-actin to form spectrin-actin arrays 1,2 . Mammalian neurons express the most diverse repertoire of spectrins, which Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms *

AbstractNeuronal morphogenesis involves dramatic plasma membrane expansion, likely fueled by SNARE-mediated exocytosis. Distinct fusion modes described at neuronal synapses include full-vesicle-fusion (FVF) and kiss-and-run fusion (KNR). During FVF, lumenal cargo is secreted and vesicle membrane incorporates into the plasma membrane. During KNR a transient fusion pore secretes cargo, but closes without membrane addition. In contrast, fusion modes are not described in developing neurons where plasma membrane expansion is significant. Here, we resolve individual exocytic events in developing murine cortical neurons and use new classification tools to identify four distinguishable fusion modes: two FVF-like modes that insert membrane material and two KNR-like modes that do not. Discrete fluorescence profiles suggest distinct behavior of the fusion pore with each mode. Simulations and experiments agree that FVF-like exocytosis provides sufficient membrane material for morphogenesis. We find the E3 ubiquitin ligase TRIM67 promotes FVF-like exocytosis. Our data suggest this is accomplished in part by limiting incorporation of the Qb/Qc SNARE SNAP47 into SNARE complexes and thus, SNAP47 involvement in exocytosis.

Highlights d Unsupervised classifiers identify four exocytic classes in developing neurons d FVFi and FVFd modes insert membrane material; KNRi and KNRd do not insert membrane d TRIM67 limits SNAP47 SNARE complexes, promoting FVFi and membrane expansion d SNAP47 incorporation into SNARE complexes delays fusion pore expansion or closure

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