Update from the laboratory of Dr. Elizabeth Neufield – November 2010
For many years, we have focused on two questions: why is the brain so severely affected in patients with Sanfilippo syndrome, and how can we develop treatment for this disease, using our mouse model of Sanfilippo syndrome type B (MPS IIIB)? We believe that we are now close to an answer to both questions.
The primary defect in Sanfilippo syndrome type B is mutation in NAGLU, a gene encoding a lysosomal enzyme needed to degrade heparan sulfate and the resulting storage of heparan sulfate in lysosomes. The original hypothesis was that the storage itself caused disease, perhaps because the enlarged lysosomes occupy a lot of space within the cell. But it has seemed paradoxical that the storage of a large amount of heparan sulfate in lysosomes of the liver and kidney don’t cause liver and kidney disease, while the storage of much smaller amounts of heparan sulfate in the brain cause profound mental retardation and dementia in patients with Sanfilippo syndrome. We reported last year that the pathology in the MPS IIIB mouse brain was much more complicated than just lysosomal storage of heparan sulfate.
Briefly, the MPS IIIB (and also MPS IIIA) mouse brain accumulates a number of substances besides heparan sulfate. Of particular interest are proteins that are known to aggregate: lysozyme, amyloid beta and hyperphosphorylated tau (P-tau). The last two are known to accumulate in Alzheimer disease. But the Sanfilippo syndrome is not full blown Alzheimer disease: First of all, in Sanfilippo syndrome these substances accumulate mostly in a very small area of the brain, called the medial entorhinal cortex, whereas Alzheimer disease starts in the human equivalent of this area but then spreads to other parts of the brain. The P-tau in our MPS IIIB mice is detected by some but not all antibodies generated against Alzheimer P-tau. And finally P-tau and beta amyloid aggregates found in the MPS III B mouse are smaller than those found in Alzheimer disease, as determined by their staining properties. Nevertheless, the presence of amyloid beta and P-tau aggregates in the MEC (and of one form of P-tau in the dentate gyrus) is significant because MEC and the dentate gyrus are very important areas for learning and memory. The aggregates of amyloid and especially of P-tau may interfere with some of the pathways needed for forming memories.
The view that the accumulation of heparan sulfate starts a pathogenic cascade that ends in the accumulation of aggregates of amyloid beta and P-tau suggests possible treatments. We are specifically looking for small molecules that can cross the blood brain barrier. Any compound that would reduce the accumulation of heparan sulfate should be beneficial. Genistein might be such a compound, as would be compounds specifically synthesized to interfere with the biosynthesis of heparan sulfate. But it would also be necessary to have compounds that act toward the end of the pathogenic cascade. Last year we reported trying lithium chloride because it was a good inhibitor of the enzyme GSK3beta, which is responsible for the formation of P-tau; but at the time the experiment had not been successful. We then tried another dose of lithium chloride, which did produce a significant lowering of P-tau in the dentate gyrus, though not to normal levels. Since lithium chloride has significant problems of toxicity, and its effect was only partial, it is not recommended for testing in Sanfilippo patients.
However, there are drugs being developed for Alzheimer disease that work by preventing the aggregation of P-tau and/or breaking up the aggregates once formed. We are testing one such drug at this time and are planning to test others. But inhibiting one step at a time is not likely to produce the optimal treatment. We believe that it will be necessary to use a combination of drugs, working at the beginning and the end of the pathogenic cascade, and perhaps at some intermediate steps as well, in order to significantly affect the course of the Sanfilippo syndrome and make a difference in the quality of life for the children. Any promising strategy developed with the mice will be brought to the attention of our clinical colleagues to work toward a clinical trial.
This work was made possible by grants from The Children’s Medical Research Foundation and from the National Institutes of Health.
Everyday, I take the train into downtown Chicago and walk nearly a mile to get into my Michigan Avenue office. Although some days I have to dodge the unruly cab driver, here or elbow my way through Union Station, the city’s beauty never ceases to amaze me.
However, what amazed me more was the passion Kirby’s special ed teacher showed toward her students. I don’t know if I could name another person who’d be willing to take a class full of wheelchair-bound students downtown on public transportation. Yes, that means loading all the students on a train, navigating through the bustling Union Station, and making that mile-long trek to Michigan Avenue. All so that each of these students could enjoy the beauty of Millennium Park. So, naturally I took the opportunity to step out of the office and enjoy the afternoon with her.
It felt so incredible to know that Kirby spends her days with a teacher who is so devoted to her students experiencing life like any other high school student. So, as I walk to work each day, I’m so grateful that Kirby is in the hands of a woman that helps her explore this beautiful city.
The Foundation is actively seeking new participants for The Seventeenth Annual “Fore Kirby” Golf Fun Raiser.
Date: Friday, June 1, 2012
Where: Ruffled Feathers Golf Club
How will the proceeds from the Golf Fun Raiser be used?
Your contribution will help us to fund researchers currently seeking funding from The Children’s Medical Research Foundation, Inc. to continue their work toward a cure for Sanfilippo Syndrome. All expenses for this event will be paid by the Foundation’s founders, Sue and Brad Wilson, and the players. This means that 100% of your donation will go directly to the Foundation. The Children’s Medical Research Foundation, Inc. is a public 501 (c) (3) charitable  corporation so your gift is tax deductible under the IRS code.
How does the Golf Fun Raiser work?
Approximately 24 golfers will secure pledges from their friends & associates for each of the 18 holes of golf they will play. Upon completion of the round, score cards will be collected from each player and the Foundation will then contact all of those who have pledged with the results of the their player’s round & the total amount due.
Interested in joining the fun? Please contact Sue at (708) 784-0631 or curekirby@sbcglobal.net to learn more.
From the early days when we found only one researcher in the world working on a cure for Sanfilippo, to today when we face an exceptional opportunity, our mission to find a cure has never been more defined. Please join us in our mission to find a cure for Kirby and other afflicted children. We chose to fight this disease. Let’s take our biggest step together. Donate what you can, whether it be a dollar, five dollars, or one hundred. Then, tell friends and ask them to do the same. Help us to make a cure for Sanfilippo the next YouTube sensation.
This past week we celebrated Kirby’s 20th birthday. As the day approached, I couldn’t help but have some bittersweet feelings. I thought back to the story my parents tell about Kirby’s diagnosis, when the doctor told my parents, well, enjoy her while you have her. On that day, none of us knew what to expect or how long Kirby would be with us. After that day, we were all scared as to what the future may hold.
However, over the years we learned to celebrate Kirby’s achievements and shift our definition of success. We learned to celebrate all that we have learned from Kirby, and find happiness in the time we share with her. So, on April 15, 2011 we did just that. We celebrated with friends new and old.
Kirby gained a new friend, Abi who shared her passion for baking with our family. It felt wonderful to know that even a person who has only known of Kirby for a short time, wanted to make her day special. Abi’s Scrumdidiliumptious cupcakes filled all our bellies and really got the party started.
While in Kirby’s classroom, it was wonderful to see how hard her teacher, Jackie Gay worked to include Kirby in activities that other kids her age would enjoy. With that said, I must confess that after 13 years of competitive tennis, Kirby did beat me in Wii Tennis. But really, who would have thought that a special education classroom would have a Nintendo Wii and an iPad for the students to use in classroom activities? Kirby is truly in an amazing place. Jackie, also surprised us by giving Kirby’s wheelchair a birthday makeover, with pink sparkles everywhere. After that, Kirby really looked like a true birthday princess.
Kirby’s birthday celebration continued that evening with a pizza party and even more baked goods from our wonderful neighbor, Claudia. The evening’s celebration was wonderful as our whole family came together to just spend time relaxing with Kirby.
At the end of the night, I looked back on the day. It was incredible to see how many people came together to make sure Kirby had a wonderful day. Kirby had a house full of flowers, gifts and cards, a decorated wheelchair, baked goods from new and old friends, and a group of friends and family that were willing to do anything to make her day special. On that one day, I didn’t think a second about the uncertain future. All I thought about was Kirby, and I was truly happy.
