Gene Therapy to Address Unmet Needs in Neurology



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.

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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.

Link back to webinar


Hi - This is Xandra, Happy to answer questions.


Hello this is Miguel. Looking forward to your questions.


Hello everyone, this is Charlotte. Delighted to respond to questions about SMA therapeutics.


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?


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


Are there any health risks that comes with AAV9 vector injections?


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


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.


After exposure to AAV9, patients will develop antibodies thus precluding re-dosing.


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


Another longterm risk is potential integration into the host genome.


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.


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


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


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.


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.


Are there AAV-mediated gene therapy clinical trials for ALS?


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.


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?