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Is the use of stem cells or cord blood going to be used in clinical trials?
At this time, it is difficult to think of how stem cells or cord blood may be used in AS. The simple fact is that stem cells work where there is acute injury or dysfunction (i.e. Parkinson’s), but AS appears to be a global change throughout the brain. We simply cannot replace all the neurons in the brain with those containing a functional Ube3a gene. Technology may advance to a place where stem cells can be used in the future in a way unknown today, but there are no plans, nor is there any reason to believe that it would be helpful, to use stem cells to treat AS.
Are there any tests available or research involved in clinically diagnosed AS patients at this time?
There is no ongoing research that I know for the small 15% of clinically diagnosed patients. However, we are finding more targets of UBE3A that may be altered in those specific cases, such as CaMKII and ARC. There is no testing yet available to determine if a mutation in another protein is “downstream” from the Ube3a protein. Regardless, we are looking into possible therapeutics that would overcome the neuronal alterations caused by Ube3a deficiency. In essence, those therapeutics wouldn’t distinguish between AS caused by a UBE3A deletion or a change somewhere in a different “link of the chain” elsewhere in the neuron.
I read an article a few months ago that you were going to begin the use of AAV as a possible treatment. I also wanted to know if anything had been tested on the adult mice with AS?
First, we have determined that when the maternal gene is disrupted in the mouse model there is a global decrease in paternal UBE3A to barely detectable levels. The idea that the UBE3A protein is only missing in certain areas of the brain is simply not true. This means that a viral therapy, stem cell therapy or region specific strategy is unlikely to work.
Second, we have used the viral mediated gene replacement strategy to replace missing UBE3A protein in the hippocamus of the AS model. This treatment shows expression of UBE3A in most of the neurons. No change is seen in motor coordination, activity or anxiety, but these mice appear to learn the cognitive test just as well as typical mice. So while the viral particles did not completely replace the protein in all of the brain, it was enough to get the animals to learn with just a subset expressing UBE3A. This tests were performed in adult AS mice!
This suggests that as a proof of concept a treatment in the adult, for at least the cognitive disruption, should be possible for human AS. We are currently working on ways to 'turn-on' the paternal gene. This should act very much like the viral treatment.
Is targeting the CamKII enzyme a viable target for a therapeutic?
We have tried to follow up on the CaMKII question, but there are several caveats to looking at this enzyme as a therapeutic target. First, CaMKII is highly regulated in the neurons of the brain and perform many functions that are just now being understood. Second, there are no available CaMKII activators, only inhibitors. This would be needed because the enzyme appears to have a decreased activation. Finally, the alteration in CaMKII appears to be brain region specific. Thus, even if an activator is found you may have a situation where more CaMKII activity in other brain regions could be more detrimental then decreased activity in the hippocampus.
I would like to know what were the advances in the research with the protein Reelin andif other research has been done regarding Reelin as a therapeutic. I’ve checked the websites www.cureangelman.org and also www.pubmed.com but I haven’t seen any news.
The use of Reelin for a potential treatment was simply serendipitous as I research the role of Reelin in normal learning and memory. What makes Reelin so potentially exciting is that it appears to act on many of the molecular changes we see in the mouse model (decreased spines on neurons, decreased AMPA receptors, decreased synaptic plasticity, deficits in learning and memory, changes in NMDA receptor-dependent long-term potentiation). We are finishing up the evaluation of Reelin in the AS mouse and hopefully a timely publication will be announced.
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