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As you are well aware, we know that what causes more than 95% of cases of SIOD is the inheritance of two mutated copies of the SMARCAL1 gene. (Dr. Boerkoel, MD, PhD, is the doctor and scientist who discovered that it was the defect in the SMARCAL1 gene that causes SIOD) However, the normal role of SMARCAL1 in the body and how deficient function of the SMARCAL1 protein causes the disease are not well understood. Much of our scientific research will focus on better understanding exactly how, and through what mechanisms, this mutation affects the body. One major breakthrough we had in the past year, which we accomplished using cells donated by Kruz and Paizlee, was to show for the first time that SIOD patients do in fact have shortened telomeres, as we had suspected. The telomere, if you remember, is like a special protein cap that fits on to the ends of the chromosomes, and keeps them from getting damaged when a cell divides and replicates all its genetic material. When telomeres are too short, there is a greater chance of damaging the chromosomes. Shortened telomeres have been associated with increased risk of cancer, and may also be a factor in other chronic diseases. This is a very important discovery in part because it links SIOD research to telomere research in general. Because defects in telomeres are responsible for a range of diseases, there are currently many scientists exploring this field, including possible ways to intervene and correct for shortened telomeres. I am confident that we will be able leverage some of this new research to help children like Kruz and Paizlee.

Now that we know that SIOD patients have shortened telomeres in one kind of cell – the T cells – we will start to explore whether or not other types of cells in their bodies have a similar defect. To do this we are going to capitalize on all the exciting new things we are now able to do with stem cells. Stem cells, as you may know, are a special kind of cell that have become key to scientific research because they are something like a “blank slate” cell, that can differentiate into many different types of specialized cells (such as a muscle cell, or a brain cell). Using stem cells from patients with SIOD, we will be able to re-create specialized cells and study how they behave, especially when compared to the same cells from a person without SIOD. This is a key tool in our arsenal. With it we will be able to zero in on an SIOD patient’s endothelial cells (the cells that line the insides of blood vessels), and hopefully understand how they work. This will be particularly important in trying to prevent some of the problems with blood vessels such as atherosclerosis (clogged arteries) and strokes, that as you know, SIOD patients face. I have also initiated a collaboration with an immunologist at UCSF, to investigate how the SMARCAL1 mutation affects T cells specifically. We know that SIOD patients have fewer T cells than healthy subjects, but we are trying to understand whether those patients’ T cells behave differently as well. This model of SIOD disease may allow us to determine if T cells can be used as an assay for treatments that reverse SIOD disease. In my discussions with Dr. Matt Might at UAB, he agrees that this might be good start also for screening purposes, and we will be talking with him regularly about our progress and to solicit advice.

Davis B. Lewis, MD

March 1, 2018   Dr. David Lewis Update

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