Gene Therapy to Address Unmet Needs in Neurology



I am not aware of AAV gene therapy trials in ALS that are currently ongoing. There is lots of interest in this however. There are ongoing trials of ASOs to knockdown mutant SOD1 in familial ALS patients.


For instance for the longest time the knowledge in the field is that we don’t have good AAV capsids to transduce oligodendrocytes in the brain. This was based on the use of AAV vectors encoding GFP under a CMV or CBA promoter. However when oligo-specific promoters were used, in fact it appears that there are several capsids that transduce oligos quite well. It is important to always consider that our knowledge of tropism is a combination of AAV capsid properties as well as promoter functionality in particular cell types.


There are also ongoing trials of ASOs to knock-down huntington in Huntington’s disease.


How does efficacy of transduction change with age? Are the neurons of a 60 year old less amendable to AAV that those of an infant? Thanks!


And I think ASO clinical trials are also underway for myotonic dystrophy and Duchenne’s muscular dystrophy.


Submitted Question:

Have any viral vectors to knock genes in vivo using CRISPR-based strategies in the adult brain efficiently been developed?


Great question. In mice it definitely does. I am aware of one paper comparing transduction in young and adult mice after direct infusion into either the substantia nigra or striatum and there are differences. Also there is a paper from Aravind Asokan showing changes in distribution of a water channel with age that affects considerably the distribution of AAV delivered into CSF. Also we know that delivery of AAV9 in neonatal mice is more efficient than in adult mice, but this difference appears to be more moderate in non-human primates. However to my knowledge there are no studies comparing systemic delivery in young adult mice vs 1-1.5 year old mice, which of course may be critical for translation to neurological diseases with late onset. Really important studies that need to be done.


Submitted question:

What is the current state of non-viral approaches?


Yes Feng Zheng in some of his papers has shown this to work quite well, but done before the advent of AAV-PHP.B and AAV-PHP.eB and thus done by direct intraparenchymal injection. I am sure the same strategy can be employed using AAV-PHP.eB since co-transduction of neurons and other cell types upon delivery of two vectors is quite effective. This of course only applies for the larger Cas9 proteins. For the smaller ones a single AAV vector may be enough to carry the Cas9 and gRNA.