Second Morning – Translation

I got to host the first block of the second morning, which I introduced as “The Translation Block.”  Not talking about language translation here, the term Translation in this context refers to that potentially long and expensive process to get from “good idea” to “Something your doctor can give you a prescription for.”  The four sessions in this block started off with  an excellent lessons learned discussion by Mark Bear http://www.fraxa.org/ra_Bear.aspx which Geraldine captured succinctly in another blog post, so I will add my comments on his session to her post rather than expound here, suffice to say we are very grateful that he came to share his experience with us. 

The second session was a short “recruiting” speech by our own Megan O’Boyle for her afternoon breakout session on the registry questionnaire.  For those of you who haven’t yet heard, our foundation has signed a contract with a registry provider and we are now in the final stages of creating what we hope is a comprehensive questionnaire to capture all medically relevant information about the symptoms of the syndrome to enable the next step in research.  Megan has done a boatload of work over the past year and a half both to find and to secure the right professional registry provider, and now she is hashing through all the options to determine what gets asked.  It made a lot of sense to use this opportunity to capture the input of the researchers attending (since they will be a major user of the summarized data), so Megan led a session to ask them. 

The third session was a presentation by Christine Mueller of the FDA’s Office of Orphan Product Development.  she presented a review of the Orphan Drug Act of 1983 and the incentives it provides to entice pharamceutical companies to promote the translation of therapies for rare diseases like PMS. 

The fourth and last session on Translation was a presentation by Chris Winrow on the challenges associated with Neuroscience Drug discovery.  His data showed that only about 11% of all Neuroscience Drugs survive the development process; there are major hurdles that include the fact that mice are “very close” to humans genetically but “worlds apart” neurologically, and the basic issues that we still face in terms of fundamental lacks of understanding as to how the human brain actually works.  In terms of personal growth I got to learn a whole new vocabulary of keystone concepts in this field:  Toxicity tests to see how much the body can stand; Efficacy measures to quantify the degree of improvement a drug provides in relation to dosage; Affinity which I took to mean how well the drug goes to the place it is supposed to; and about a dozen others.  One of the more interesting concepts was “Subjectivity”, which means “Does the drug make you feel better”.  The example Chris used was a hypothetical sleep aid that might make you go to sleep quicker and sleep more soundly, but if you wake up feeling like crap it would be a bust on the subjectivity scale because no one would buy it (or at least no one would buy it twice).

Lots of food for thought.

First Afternoon – Tools and Barriers

The first day finished with a flourish, what an exciting afternoon!  We heard first from Jacqueline Crowley from NIMH http://intramural.nimh.nih.gov/research/pi/pi_crawley_j.html, she gave a really excellent review about what they have seen in the Shank3 knockout mice (the whole gene in this mouse is not knocked out like our kids, rather they inserted a mutation into the Shank3 gene which is designed to make the gene non-functional, so the proper term is “knockdown”) developed by Dr Buxbaum’s lab.  It is very exciting that there are now several mice (see below) that have been developed to model PMS, with testing underway as we speak to characterize and analyze them to validate them as tools for further research.   She presented the results of a broad range of testing they have done on these mice, with some interesting phenomena observed.  They are now at the point where the reserachers working with the mice are very interested in knowing details of how our kids behave and interact so that they can correlate what they see in the mice to what we see in the syndrome.  Dr Crowley showed positive results in a test called the rotarod, in which the mouse is put on a wheel that rotates progressivley faster until the mouse falls off, a test of coordination.  With time and repetition the (normal) mouse learns to get better at this test, but the Shank3 knockdown mouse starts at a lower level of capability and learns more slowly, but does eventually catch up.  They also tested a “double knockdown” mouse that has both copies of Shank3 impaired, and it started with even less capability, learned very slowly, and never quite caught up.  The other interesting resutls that they got were low scores on “following” (moms who are familiar with this phenomena in grocery stores take note) and high scores on “avoidance” behavior (how many of us have been told that by their therapists?)  There was no difference on some basic survival skills type testing they did called a water maze in which the mouse has to swim around in a tank until it finds an submerged platform to rest, the knockdown mice were as good at this as the regular mice.  The researchers are now very very interested in learning more about our kids’ behavior, this is very timely to our registry development effort (more about that on Friday afternoon from Megan’s session), so we need everyone to participate when we launch that later this year, the researchers need this data now. 

The afternoon finished off with two roundtable discussions which were fascinating.  The first was a discussion led by Dr Buxbaum on the what is needed to advance the prevention and cure of PMS.  Dr Buxbaum broke the probelm down into three questions – What barriers are in the way?  What can researchers do to mitigate these barriers?  and What can the foundation do to help? 

The second roundtable discussion was a highly interactive discussion between all of the reserachers (5 different groups!!) who are working on mouse models about the types of models they are developing, the issues they’ve had, and the progress they’ve made.  If I kept count correctly, there are 9 (wow!) mouse models that knock down the Shank3 gene partially and completely.  Dr Boeckers discussed the Ulm mouse, which took them 3 distinct efforts to get one that could reproduce, and which they are working to understand.  Dr Buxbaum talked about the mouse model they developed, and explored some of the practical problems they had and how they overcame them.  Craig Powell from UT Southwestern http://www.utsouthwestern.edu/findfac/professional/0,,51488,00.html has worked on a total of 3 mice, 2 of which have been published and the 3rd of which will be published soon.  We also learned that 3 different mice have been developed by Yong-Hui Jiang’s lab at Duke University, he discussed some of the results his lab is noting with respect to expresssion of Shank3 splice variants.   Lastly, junior investigator Michael Wells (who won a PMSF travel stipend to attend) discussed a knockout mouse developed in Dr Guoping Feng’s lab that will be published in the journal Nature http://www.nature.com/ very soon, online this week and in print later in the month. 

After those two roundtable sessions, we adjourned to the poster session.  We had 8 posters presented, addressing a wide variety of aspects of the syndrome from large scale statistical analysis of physical aspects and deletion size by Sara Sarasua of Greenwood Genetics Clinic to the very micro scale analysis of zinc’s influence on Shank1, Shank2, and Shank3 expression patterns in neurons by Andreas Graebrucker from Stanford and Ulm.  Danae Papapetrou from Mount Sinai presented an excellent poster on an analysis of the neurons of one of the knockdown mice exploring how reduced Shank3 levels negatively affects recruitment of Glutamate and the formation of AMPA receptors in the neuron.  Michael Urbanski from Hunter College presented his work on IB2, the gene next to Shank3 on the chromosome and also interacts with Shank3 in the synapse, they have developed IB2 knockdown mice and are characterizing them.  Chiara Verpelli from Dr Sala’s lab in Milan presented their latest work with a Shank3 knockdown mouse, her investigation showed that Shank3 deficiency affects expresssion of a glutamate (mGluR5) in synapses, another potential lead on solving the effects of Shank3 deletion.  Mu Yang from NIMH presented the results of the behavior investigation of Mt Sinai’s Shank3 knockdown mouse, further exploring the material Dr Crawley discussed earlier the day.  Kolevzon’s poster addressed the link between PMS and autism through evaluation of several children with PMS against multiple diagnostic criteria.  It was very interesting and rewarding to talk to all of the young investigators about their work, their energy and interest is very motivating.  The Interim Scientific Advisory Committee evaluated all 8 posters against a pre-determined criteria, and it was very close scoring due to the high quality and content of the presentations. Sara Sarasua was chosen to receive a $1000 award in recognition of contribution to the understanding of Phelan-McDermid Syndrome.  Congratulations Sara! 

After the poster session and reception we retreated to the hotel, and several of us spent some wonderful socail time talking about life, research, and PMS with the research team from Ulm in the lounge at the Marriott.  Big day!

Lessons learned from Fragile X

We just heard from Mark Bear (Fragile X researcher). His mGluR theory of Fragile X has resulted in drug compounds for fragile X. Here is his advice for our community:

• Easy availability of animal and test compounds
• Build collegiality and trust among principal investigators. Fragile X community held intimate meetings of 20-25 PIs, where they talked openly about what they were doing. Stuff that was published was way old news among the PIs who participated in the meetings.
• Encourage top labs to participate to raise quality of science. FRAXA appeared to reach out to labs by offering fellowships.
• Spread funding broadly to encourage participation and reduce competition – broadening the community of people interested In the disease
• Give endeavor a human face. The follow up of the parents to the investigators was meaningful.
• Rigor – test targets rigorously because stakes are high
• Encourage replication of findings
• Encourage pharma but don’t assume bigger is better
• Entrepreneurship may be required

Autism Diagnosis

Dr. Alex Kolevzon of the Seaver Autism Center at Mt. Sinai presented a poster with the results of the clinical research study they are doing. Out of the 18 PMS patients they have seen, 80% meet diagnostic criteria for ASD. Although their study has a small sample size (it is growing), the finding of ASD in such a high percentage of PMS patients is important, and would suggest that PMS patients SHOULD be evaluated for ASD.

First Morning – PMS, Autism, and SHANK3

We just broke for lunch, what a morning.  Sue Lomas kicked things off with a great introduction talk, covering some of our family and foundation background and history (7 families in 1992 to over 600 now) and setting a very high and hopeful bar for all of us with a “where we’ve been, where we are, and where we’re going” tone.

Katy and Curtis shared the first session presenting “Identification and manifestations of PMS”, with updated versions of their syndrome characteristics and identification charts to the group of families and researchers.  There were many questions by the researchers who are obviously working to mentally search for the connections between the lab results they are seeing in their cell cultures and mice to the range of large scale issues our kids are dealing with.

Next was Catalina Betancur from France, who talked about the correlations she has identified between SHANK3 deletions, duplications, and mutations to broader diagnoses with a focus on autism.

This was followed by a very in-depth presentation by Carlo Sala from Italy http://www.in.cnr.it/project_data.php?PID=49 on the functions of SHANK3 in neurotransmission.  He covered a lot of ground and I struggled to keep up, but will post more later when I have a chance to decipher my notes a bit.

Right after Dr Sala was a presentation by Tobias Boeckers from Germany, covering the whole family of Shank genes and what his lab is learning about the roles they play in both “normal” neurology and in neuropsychiatric disease.  Will post more on his presentation later as well, got to run to Jacqueline Crawley’s presentation on Shank3 mutant mice now.

Randy

Speakers Dinner

Last night we met several researchers at the Metrazur Restaurant in Grand Central Station for dinner, http://www.charliepalmer.com/Properties/Metrazur to spend some time with some of the researchers who will be speaking at our conference today.  The dinner was absolutely incredible (I highly recommend the Pork Tenderloin w/ artichoke hearts and the Bittersweet Chocolate Cake with lemon siding), and the socializing went so long we closed the place down (and the staff with very patient with us).

It was great to meet several of the researchers who we’ve corresponded with over the years and whose papers we’ve been reading and whose research we’ve been following for years, to get to know them a little before they speak to us and their peers across many disciplines today and tomorrow.  I shared a cab (and later a table) with Tobias Boeckers and two of his researchers from the Univeristy of Ulm in Germany, http://www.uni-ulm.de/en/ and chatted over dinner with other researchers from Duke University http://research.duke.edu/, MIT  www.web.mit.edu/research, and Hunter College http://www.hunter.cuny.edu/research/ about the research efforts they are undertaking in the Shank gene family (Shank1, Shank2, and Shank3), mouse models, gene functions, and phenotypes.

In talking with these researchers, I was very touched by their interest in our families.  As one researcher put it, “When I decided that my area of research would be the Shank genes and the theory of how they function in human nervous system, I never had the slightest idea that a parent would read one of my research papers and make contact with me to ask questions about how what I was doing might help their child.  This is extremely motivating and uplifting, and is a surprising turn in what I thought would be a pretty purely scientific career.”  Wow.

Gotta run, sessions are starting…

It’s Almost Here!

Wow.  It is incredible to think that this long-dreamed event in the lives of our children, our families, and our foundation is almost here!  Words are insufficient to pay proper homage to the magnitude of this conference for so many in our small community, but I feel am called to give it my best shot out of respect for the labor of love by those who have brought us here. 

In order to keep this short in the spirit of good blogging, I’m just going to talk about three people in this opening salvo, more victims to be added later.  🙂  Gotta start with our Research Chair Geraldine Bliss, Charles’ Mom, that a woman of immense organizational talent and bottomless energy that has pulled everyone together (and gotten everyone to pull together) to make this conference happen.  Geraldine came charging in and grabbed the reins of the Research Committee when we were in dire need, she got us energized, organized, and documented and set off marching hard toward this international gathering of professionals dedicated to research of many kinds that touch the lives of our children now and in the future.  

Second on my list and beloved by us all is Sue Lomas, Sam’s Mom.  She who stepped up from the ranks of scared parents to organize us from rabble to support group to 501(c)3  non-profit foundation on the strength of her will and the love in her very big heart.  She very literally took every one of us by the hand and created a support group where families who felt so alone yesterday can find new friends who’ve been there, destined to become old friends who gather every two years to catch up on everything from puberty to iPads.

Last on this list but right out front from Day 1 is of course Dr Katy Phelan.  She forged the initial links, both genetic and contact, that brought us together for the first time and so many times since then.  She is our first lady of research, a real class act, and a PhD you can share beers or a Harley ride with, and she does a real convincing Maleficent on Halloween.  From her initial research to identify the syndrome years ago to calls to physicians to help our kids in real time today, she has touched all our lives. 

As I print my boarding pass and start packing my suitcase for NYC, I am humbled by the immensity of what is about to happen.  We just went over the 100 people registrants mark today, from dozens of different labs and a dozen different disciplines.  All of these people from all over the world are going to be talking and thinking about Phelan-McDermid Syndrome for the rest of this week – making plans while traveling to the conference, taking notes on ideas and inspiratuions at the conference, organizing their ideas into plans on their way home.  I have grand hopes that bringing these researchers and stakeholders together will provide the insightful sparks that generate new research and turn current research in new directions to answer the many questions we have about how the genetics of this syndrome cause the symptoms our kids share, and plant the seeds of new studies of potential treatments to provide solid improvement in our childrens skills and conditions.  Hope is HUGE tonight.   Randy Riddle

1st International Phelan-McDermid Syndrome Symposium

I am very excited about the upcoming symposium.  We have a fantastic agenda and speakerlist.  The symposium will be held March 2-3 in New York City.  To learn more, please visit the symposium website.