SIOD RESEARCH
 

December 2024 Update:

Jessica and Kyle, you are driving first-of-its-kind research.

For nearly eight years, you have spurred vital research for families facing rare genetic diseases. We are grateful for your vision and partnership between Lucile Packard Children’s Hospital Stanford and your home communities in Muscle Shoals, Alabama, and Palo Alto, California.

Together, your generosity has surpassed $3.5 million through the Kruzn for a Kure Foundation—an incredible feat.
This philanthropy has made possible a series of firsts for children with Schimke immuno-osseous dysplasia (SIOD): the first dual immune/solid organ transplants, news of which was published in 2022; and the development of new induced pluripotent stem cell (iPSC) lines to model SIOD, which was completed in 2023. And now, the first “cell painting” of SIOD, a research analysis technique you’ll learn more about in this report.
Your contributions to science have been personal. The iPSC lines derived from Jessica and Paizlee’s blood cells have enabled the most advanced modeling of SIOD ever undertaken, bringing us potential answers for dealing with stroke prevention not only for over a dozen children with this rare disease in the United States, but foreseeably anyone at risk for stroke due to atherosclerosis. Your latest push for fundraising is launching a new phase of investigation for SIOD therapeutics, in which we are focusing on developing therapies to prevent strokes.

Thank you for your courage and steadfast pursuit of better health outcomes for your family and for humankind.
With gratitude for all of the amazing efforts you’ve made on behalf of children with SIOD,

David B. Lewis, MD
​Professor of Pediatrics
​​Chief, Division of Allergy, Immunology, and Rheumatology
​​Stanford School of Medicine

 
At your suggestion, in 2024 Dr. Lewis reached out to Matt Might, PhD, the director of the Hugh Kaul Precision Medicine Institute at the University of Alabama at Birmingham, for guidance on how best to leverage Stanford's newly developed human cell line of SIOD. In turn, Dr. Might is the one who introduced the Lewis Lab to a pioneering analysis technique called a cell painting assay.
 
What is cell painting?
 
First developed in 2013 by Anne Carpenter, PhD, a scientist at the Broad Institute of MIT and Harvard, a cell painting assay is a high-throughput imaging technique that uses fluorescent dyes to analyze the structures of cells, so that nuclei light up as blue, mitochondria as red, endoplasmic reticulum as green, and so forth.
As Dr. Carpenter said in an interview with The Scientist: “As a cell biologist, I felt that labeling the major organelles would probably give us the broadest readout of how the cells were experiencing their environments.”
 
The merit of cell painting for SIOD researchers is the sheer volume of data. This standardized approach takes cells of interest and cultures them using 10 plates that each have 384 wells. Every well contains a couple thousand cells, and every cell is analyzed for 10,000 features.
Using automated analysis, Dr. Lewis and his team can sift and sort through the data, comparing the observable traits of SIOD with tens of thousands of other publicly available cell painting assays for different medical conditions—looking for clues. Other diseases that share similar phenotype signatures could lead the way to drug candidates for SIOD.

“As far as I can tell, we are pioneers in using these endothelial cells in cell painting assays,” says Dr. Lewis of the cells lining the blood vessels and lymphatic vessels. When creating the human cell model of SIOD, he and his team turned induced pluripotent stem cells into endothelial cells. This is allowing the researchers to examine how the condition impacts arteries, veins, and capillaries in kids with SIOD, given their elevated risk of stroke.
“This is potentially a way of turning the disease into a tool we could use to screen for drug therapies. We had to reduce the complexity of the disease in the living body to something that we think is representative of the disease mechanisms in tissue culture.” - Dr. Lewis

 
In February, the Lewis Lab will be applying for a Foundation Award for Discovery-Stage Research from the California Institute of Regenerative Medicine (CIRM). The team has been spending months preparing preliminary data and findings for the grant.
We’ve been throwing everything at it,” says Dr. Lewis. “The plan is to ask for at least two to three years of funding to get support for developing a drug that targets and prevents the strokes associated with SIOD. So, we’ve really pivoted for this philanthropy.”
 
What would the CIRM grant help to accelerate?

• Basic science: Allowing researchers to better understand SIOD and verify results from lab models with real-life patient experiences and biology.

• Drug screening: Letting scientists screen existing therapeutics very efficiently, up to 2,000 compounds at a time, in search of drugs that can benefit SIOD patients.

• Clinical trials: Beginning trials with children who have SIOD, using the most promising drugs discovered.

Researchers in the Lewis Lab especially hope to compare proteins in blood samples from SIOD patients with the engineered endothelial cells, and anticipate seeing the same proteins altered in both places. While Dr. Lewis doesn’t yet know for sure what they will find comparing the human blood cells with the tissue culture designed to mimic the SMARCAL1 deficiency, he believes it could be a critical step toward validating their disease model.
 
“Our hope is that all of the abnormalities associated with SIOD reflect a common problem that may be correctable by a single drug therapy.”
David B. Lewis, MD
 
Thank you, Jessica and Kyle.
Because of your visionary leadership, and the contributions of everyone in the Kruzn for a Kure community, we are laying the groundwork for a better tomorrow for children with SIOD.
We will keep you informed of the results of the CIRM grant application. Thank you, as always, for everything you have made possible to bring us to this moment.
Michael Tomura
​Associate Director, Major Gifts