Saturday, April 6, 2013

ABA, Gargus and Research Ideas.

Yesterday, Luki got his first ABA evaluation.  It was pretty lengthy and comprehensive and he has another one on Wednesday.  It was so sad to answer "no" to so many of her questions.  "Does he feed himself? Does he play peekaboo? Does he point to things? Does he say mama or dada? Does he acknowledge his name?" No, no no and no.  To me, Luki is perfect, but after having answered no to so many of these questions, it just reminded me of how very different he is from regular babies.  I worry that the ABA program would be too harsh for him or that it would give him OCD.  But, I know at this time, this is the best for him.  He gets very frustrated and stressed when he is made to do things and I hope the program does not stress him out too much.

Last Wednesday, I also had my first meeting with Dr. Gargus and G. Calvert to discuss future clinical trials for the IDIC 15 population in the Alliance's registry.  He stated that he is interested in looking into a mitochondrial connection to autism, calcium channelopathy and plans to purchase sophisticated EEG machines and conduct sleep studies - all very relevant to Luki's condition.  When I brought up my concern about a possible lipid metabolism problem, he stated that his group is working on a lipid molecule from marajuana that seem to reduce autistic behavior.  I am looking forward to more research and results for testing of this molecule - eicannocannibus?  can't remember the exact name. Although the IDIC 15 clinic was just launched at UCLA, Dr. Gargus said UCLA has a much smaller autism research and treatment center compared to UCI and it caters to wealthy families that may not even need insurance to pay for services.  This was one concern I had about taking Luki to the new IDIC 15 clinic.  How much would it cost us as it would have to be out of pocket since UCLA is out of Kaiser's hub of providers. 

We invited Dr. Gargus to the annual scientific conference at UC Davis Mind Center and he hooked us up to Dr. Kimonis who is heading up the Prader Willi study at UCI.  I hope to meet or speak with her in the near future. 

I question if I am doing everything I can for Luki and wonder if he knows how much I love him.  I wish I could have him just say one word for me now - and an "I love you" would take me over the moon.  I wish he can tell me what bothers him, I would like to know so badly. 

Last week, I also suggested a research idea to the scientific advisory board which involved a possible inhibitor study of UBE3a gene product.  I suggested various ubiquitin ligase inhibitors be studied and assayed on  IDIC 15 brain cell lines, then given to the knock in mice and measure any improvement in autistic behavior.  I was told by Dr. Chamberlain that there are three kinds of ubiquitin ligase inhibitors and the one we are looking for (with a HECT domain) has not been discovered, yet.  This inhibitor has become my holy grail.  In the meantime, it doesn't stop us from trying other experiements on the nature of UBE3a.  Perhaps the ideas I am about to share have been tried and studies already, but if not, it is worth taking a look at.

First, I am curious to know whether the UBE3a gene products in IDIC 15 brain is stucturally and functionally the same as normal UBE3a.  Dr. Reiter's finding that the copy number dosage does not necessarily correlate with the severity of the symptoms suggests that there may possibly be a defective translational product in the presence of the extra UBE3a genes.  Could it be that the translational product of UBE3a undergoes a protein misfolding in the presence of the extra genes such that they do not perform at the same level as the UBE3a from those with a normal copy number?  Do the  subunits dimerize? trimerize? or just look and function differentlyand less efficiently than the normal enzyme?

I am wondering if it is possible to isolate the ubiquitin ligase form the IDIC 15 brain cell line (without alterring their endogenous structure in the process), and then run it on a gel to separate by size and charge and compare it to ubiquitin ligase from a normal copy numbered brain cell and see whether they actually do have the same characteristics.  Could we get even further confirmation through x ray crystallography to see the structure? 

If the gel study shows that the IDIC 15 E3 ligase indeed is different from the normal, what would be the effect of giving these cells more of the E3 ligase that functions properly?  I wonder if such a study is being done for the Angelman Syndrome. 

On the other hand, if the gel study shows that it indeed is the same as the E3 ligase in normal people, then rather than waiting for the discovery of a HECT domain UBE3a inhibitor, why not use the endogenous substrate for the enzyme, which I believe is an ARC protein. What would be the efffect of giving more of the ARC protein?  Could the ARC protein be modified so that it somehow irreversably binds to the UBE3a ligase (maybe form a strong covalent bond somewhere on the enzyme) so that the enzyme can no longer uptake more substrates thus rendering it inactive?

These are some crazy ideas I think of in the middle of the night and I hope to present them to the science advisory board.  Hopefully, it doesn't sound too far fetched and I don't offend anyone's scientific sensibilities.  If nothing else, they can get a good laugh at it. 



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