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Gene Therapy to Address Unmet Needs in Neurology


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Neurobiology of Disease Webinar and Live Chat | July 12, 2018

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Advances in gene therapy have propelled the field into the clinical realm, and new medical treatment options are beginning to offer help in neurological diseases long thought to be incurable.

In this webinar on July 12, select faculty from the 2017 Neurobiology of Disease Workshop will continue the discussion on:

  • Gene targeted therapies for spinal muscular atrophy.
  • Gene addition in hematopoietic stem-cells for leukodystrophies.
  • Adeno-associated virus gene delivery for neurological disease.

After the scientific presentations, join the speakers @csumner1 @miguel.esteves @breakefield in the replies below for a live chat. Feel free to leave your questions in the Neuronline Community in advance of the live chat. *

Register now

Watch the Webinar: July 12, 1:00 p.m. EDT

Join the Live Chat: July 12, 1:45 p.m. EDT

Can’t attend live? Register to watch on-demand.

*Current and inactive SfN members log in using SfN.org information. non-SfN members create a new account.


In the live chat:

imageCharlotte Sumner, PhD
Charlotte J. Sumner is a professor of neurology and neuroscience at Johns Hopkins University School of Medicine.

imageMiguel Sena Esteves, PhD
Miguel Sena Esteves is an associate professor in the department of neurology at the University of Massachusetts Medical School.

imageXandra O. Breakefield, PhD
Xandra O. Breakefield is a professor in the department of neurology at Harvard Medical School and a geneticist in neurology and radiology at Massachusetts General Hospital.


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  • 5 weeks later...

Submitted question:

I’m interested to know about the delivery of gene therapies. Could the faculty discuss the challenges with targeting the brain, and even specific cell types? How feasible is immune cell targeting?

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miguel.esteves

Could you clarify whether you are asking about targeting immune cells in the brain, or immune cells more generally?

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This is a very important question and our experience in humans is obviously limited. Thus far the main toxicity that has been observed is a mild elevation in liver enzymes that was easily managed with a short course of steroids. Whether more severe liver toxicity can occur is not known

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Another issue that arises is whether a patient has preexisting antibodies to AAV9. One patient was excluded from the SMA gene therapy trial because of preexisiting antibodies.

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Amanda Kimball

Is glia production of SMN1 through AAV9 injections sufficient to recover function, or it has to be produced by motor neurons?

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miguel.esteves

The present challenges in targeting the brain depend on the application. If you are working in mouse models then the new AAV-PHP.B and AAV-PHP.eB developed at Caltech are exceptionally efficient for systemic gene delivery with transduction of a large percentage of cells in the adult mouse brain. However these new capsids do not appear to display quite the same remarkable properties in other species and as such their translational potential for clinical trials is less certain at the moment.
Another challenge with achieving global gene delivery to CNS is the fact that these capsids nonetheless transduce many other tissues in the body, which may have undesirable side effects. This is where tissue/cell type specific promoters come into play as well as post-transcriptional regulatory elements such as microRNA targets to engage the RISC pathway in organs where one wants to eliminate transgene expression.

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AAV9 theoretically remains principally episomal, but integration particularly with exposure to high viral titres could result in oncogenesis.

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laura.mitic

Hi, could you please speak to advances in AAV capsids that allow robust transduction of microglia. Are there any? Thanks!

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miguel.esteves

Microglia remain one of the CNS targets that are quite difficult to target. However it is unclear if this is due to the lack of adequate capsids or specific promoters.

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miguel.esteves

After all we can only know what we can see, ie if we don’t have good promoters that are highly specific for microglia the evaluation of transduction become quite challenging and may be overlooked or not present due to promoter inadequacy.

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The existing data indicates that SMN must be induced in motor neurons to improve disease outcomes. It remains controversial whether SMN deficiency in other cell types contributes to disease. It is possible that therapeutics that induce SMN in multiple cell types will be more effective than those that principally target motor neurons.

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Submitted question:

How are eligible patients or subjects screened for immunocompetency? What is molecular and cellular target? What approach to post-gene therapy rehabilitation is recommended?

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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.

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miguel.esteves

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.

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laura.mitic

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!

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Munin Streitz

Submitted Question:

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

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miguel.esteves

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.

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miguel.esteves

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.

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