Scientists CREATE New Gene Therapy Technologies. But Can They Deliver For ALS?

A new gene delivery vehicle may help increase the efficacy of gene therapies being developed for ALS. The adeno-associated virus AAV-PHP.eB, developed by a research team led by Benjamin Deverman and Viviana Gradinaru at the California Institute of Technology, penetrates the central nervous system, including neurons and astrocytes.

A delivery for motor neurons in people with ALS? The vector AAV-PHP.eB delivers genes throughout the brain (top row) and spinal cord (bottom row) about 2 times more efficiently than AAV-PHP.B according to a preclinical analysis. A second gene delivery vehicle, known as AAV-PHP.S, which can be administered simultaneously, penetrates the peripheral nervous system, including the muscles. [Courtesy of Chan et al., 2017, Nature Neuroscience. Reproduced with permission.]

What’s more, the vector, derived from AAV-PHP.B, can transduce more than 50% of these cells using at least 10-fold lower doses (about 4 to 5 x 1012 vector genomes/ kg) according to a preclinical analysis, and is therefore more suitable for clinical applications.

The study is published on June 26 in Nature Neuroscience.

The gene delivery vehicle, identified by a capsid selection method known as Cre recombinase-based AAV selection, is one of a growing number of vectors being developed to deliver potential therapies for neurological diseases in the brain and spinal cord (see June 2017 news). This selection strategy, known as CREATE, is the same approach being used, in collaboration with Boston area startup Voyager Therapeutics in Massachusetts, to develop vectors for a potential treatment for SOD1-linked ALS. The gene therapy, known as VY-SOD101, is at the preclinical stage. The researchers previously used CREATE to identify AAV-PHP.B, a vector that is estimated to be at least 40-fold more efficient than the emerging gene therapy vehicle AAV9 in delivering genes into the brain and spinal cord (Deverman et al., 2016; see June 2017 news).

Now, the Cal Tech team hopes to create a gene therapy vehicle that can also be used to deliver genes to other key cells of the brain and spinal cord, including oligodendrocytes. These key support cells, which may boost energy supplies in motor neurons under stress, also degenerate in ALS, which may contribute to the disease (see July 2012, April 2013, November 2016 news; Nave, 2010; Lee et al., 2012; Kang et al., 2013; Ferraiuolo et al., 2016)

Meanwhile, in France, researchers are developing a new gene-targeted approach to reduce motor neuron toxicity in SOD1 ALS. The AAV10-based strategy, which involves an injection into the brain and the vasculature, silences the SOD1 gene using a U7-mediated exon skipping mechanism (see May 2017 conference news; Biferi et al., 2017). The approach, according to a 2017 analysis, increases the lifespan of SOD1 G93A mice more than 2-fold than existing RNA interference approaches. Now, Barkats team is adapting this strategy to develop gene therapies for C9orf72 ALS, the most common form of the disease.


Chan KY, Jang MJ, Yoo BB, Greenbaum A, Ravi N, Wu WL, Sánchez-Guardado L, Lois C, Mazmanian SK, Deverman BE, Gradinaru V. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat Neurosci. 2017 Jun 26. [PubMed].

Deverman BE, Pravdo PL, Simpson BP, Kumar SR, Chan KY, Banerjee A, Wu WL, Yang B, Huber N, Pasca SP, Gradinaru V. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol. 2016 Feb;34(2):204-9. [PubMed].

Biferi MG, Cohen-Tannoudji M, Cappelletto A, Giroux B, Roda M, Astord S, Marais T, Bos C, Voit T, Ferry A, Barkats M. A New AAV10-U7-Mediated Gene Therapy Prolongs Survival and Restores Function in an ALS Mouse Model. Mol Ther. 2017 Jun 26. pii: S1525-0016(17)30251-4. [PubMed].

Further Reading

Jackson KL, Dayton RD, Deverman BE, Klein RL. Better Targeting, Better Efficiency for Wide-Scale Neuronal Transduction with the Synapsin Promoter and AAV-PHP.B. Front Mol Neurosci. 2016 Nov 4;9:116. [PubMed].


*Please note: The dosage is based on an estimated weight of 21-24 g of a 6-8 week adult C57Bl/6J mouse which is according to the Jackson Laboratory.


AAV-PHP.B AAV-PHP.eB AAV-PHP.S AAV10 aav9 c9orf72 disease-als gene therapy SOD1 topic-randd vector
Share this: