Dear Kruzn for a Kure Foundation:
I want to thank all of you and your community for your extraordinary support of Schimke Immuno-Osseous Dysplasia (SIOD) research at Stanford University for the last two-and-a-half years. Incredibly, you have given more than $1.4 million towards SIOD research. With this funding, we have been able to hire research staff who can dedicate their time to focus on SIOD and start new groundbreaking investigations into how we can treat SIOD. We are extremely grateful for your entrusting us with getting this novel research program off the ground.
As you know, SIOD is due to mutations for the SMARCAL1 gene. Our goal is to develop therapies that address the multi-organ problems characteristic of the syndrome that are the result of SMARCAL1 deficiency, including decreased immune function, kidney failure, skeletal growth issues, and abnormal vascular function leading to migraines and seizures.
Expanding our Team and Developing SIOD Treatments
Your funding has allowed our lab to jumpstart research into unraveling the mystery of how SMARCAL1 protein deficiency leads to SIOD. Because of your support, we have been able to grow our lab and accelerate our investigations.
Over the last year, we’ve expanded our team, and Elizabeth Lippner, MD, PhD, has been joined by Postdoctoral Fellow Rebecca Saenz, MD, PhD; Senior Research Scientist Girija Dhamdhere, PhD; and Lab Science Research Professional, Vasavi Ramachandran, MS, to shed light on how a lack of SMARCAL1 protein causes the clinical problems of SIOD.
Your gift in February of $150,000 to the Lucile Packard Foundation for Children’s Health for SIOD research allows us to hire two new researchers at the post-doctoral fellow or research scientist level. We are in the process of interviewing for both of these positions and hope to have one of these filled no later than the end of December 2019.
Your funding over the last year supports our team’s time, purchasing of chemicals and supplies, and any costs related to carrying out investigations. Our studies could lead to developing new drugs or using ones already approved by the FDA or that have been tested in Phase III studies in human clinical trials (an approach also known as “repurposing” drugs).
Armed with a diversity of skilled scientists, we have been undertaking these experiments: We are running a full profile of the types of mRNA in SIOD patient T cells compared to healthy T cells; we are also seeing if the structure of the DNA that encodes the genes differs in SIOD T cells compared to that of healthy controls; Dr. Saenz is using gene-editing technology in the lab to disrupt the SMARCAL1 gene of a healthy T cell to determine how this affects its function; Our team is engineering customized cell lines called induced pluripotent stem cells (IPSCs) from SIOD patients, including Kruz and Paizlee, so that we can ultimately study in lab how the disease affects many types of tissues, such as the podocytes of the kidney that are involved in making urine and cells that line the blood vessels and that appear to have abnormal function in SIOD. We have also now made EBV-transformed B cell lines from all four of the Davenport family. These cell lines will help expedite studies of the mechanism of disease in SMARCAL1 deficiency by allowing us to grow the cells quickly into large numbers. This limits the number of blood draws from all of you that are required for us to carry out our work.
We plan to submit this work and Dr. Lippner’s discovery on short telomeres for publication by the end of this year. This is so important because it puts us in a strong position to apply for funding from the National Institutes of Health and other granting agencies and will also help establish a research network and collaborations with other scientists.
Making Stem Cell Transplants Safe for SIOD Patients
At the moment, we feel that hematopoietic stem cell transplant (HSCT) is the best way to improve SIOD patients’ quality of life, but as you know in the past this procedure had a very high approximately 80% mortality rate (4 out of 5 children died within 3 months following the HSCT). However, the one 7-year old boy with SIOD who survived the procedure and shortly after HSCT received a kidney from his father has had a remarkable outcome – he is now 20 years post-transplant and is in generally good health. Based on this excellent outcome, we were able to convince Alice Bertaina, MD, PhD, a world-renowned expert in HSCT of children with primary immunodeficiency to treat Kruz and Paizlee. Dr. Bertaina has pioneered using haplo-HSCT in which one of the parents is used as a donor to their child
Earlier this year, Kruz and Paizlee underwent HSCT using blood stem cells obtained from their parents. To the best of our knowledge, as we indicated above, only one patient has had a successful outcome previously. Your funding played an essential role in their carrying out HSCT for Kruz and Paizlee with a specialized protocol focusing on safety and rapid engraftment.
Using your funds, Dr. Lippner learned that Kruz, Paizlee, and other SIOD patients have white blood cells with short telomeres at the ends of their chromosomes. This discovery informed Dr. Bertaina to use a lower dose of radiation and specialized chemotherapy to prepare Kruz and Paizlee for HSCT.
Kruz did extremely well after the transplant with rapid engraftment of his stem cells and normalization of many of his white blood cell counts. As Alice Bertaina, MD, PhD a result, Kruz successfully received his kidney transplant from Jessica in July 2019, months ahead of schedule. We look forward to watching Kyle’s stem cells fully engraft in Paizlee so that she can receive a kidney transplant from him hopefully by the end of this year.
Thank You for Putting Your Faith in us.
There are so many reasons why the lab owes the success of the exciting research we are conducting to you. Because of your extraordinary efforts to raise awareness about SIOD, so many patient families have connected with us. We are going to see two new patients this year.
I want to especially thank all the amazing donors in Muscle Shoals and elsewhere who support the Kruzn for a Kure Foundation. Jessica and Kyle, I remain awed by your commitment, tenacity, and strength in building this effort from scratch! It is all because you asked us to come up with a research program to try and develop new therapy for these kids. I am immensely grateful that you have put your faith in me and my lab and Dr. Bertaina and her lab to do this important work.
David B. Lewis, MD
Professor of Pediatrics, Department of Pediatrics
Chief, Division of Allergy, Immunology, and Rheumatology
Member of the Program in Immunology and the Institute for Immunology, Transplantation, and Infectious Disease
Stanford University School of Medicine