Schimke Immuno-Osseous Dysplasia (SIOD)

In work supported by the Kruzn’ for a Kure Foundation and the Little Giants Foundation, we are pursuing studies to understand the disease mechanisms and possible treatments for a Schimke Immuno-Osseous Dysplasia (SIOD).

SIOD is a multisystem disease that has a unique disease phenotype that includes an intrathymic developmental T-cell defect with reduced T-cell IL-7 receptor surface expression, short stature due to impaired long bone growth, nephrotic syndrome due to focal segmental glomerulosclerosis of podocytes, and neurovascular disease that affects mainly the blood vessels supplying the brain.

A major medical mystery is how biallelic mutations of the SMARCAL1 gene, which is the only cause of SIOD, lead to this unique phenotype. Extensive studies in tissue culture systems have revealed that the SMARCAL1 protein plays an important role in genomic DNA replication and telomere maintenance, but the linkage between impairments of these functions and the disease phenotypes of SIOD remains obscure.

In collaboration with Matthew Porteus’ laboratory, we are currently using CRISPR-mediated homologous directed repair (HDR) approaches for genomic DNA editing to generate unique induced pluripotent stem cell (IPSC) and hematopoietic stem cell (HSC) isogenic lines involving the SMARCAL1 gene, which is biallelically mutated in SIOD.

Thanks to a major recent additional gift from the Kruzn’ for a Kure Foundation, we are now using these cell lines for studies of SIOD disease mechanisms, the development of markers for disease activity, and identifying potential treatments for SIOD. We are also using this CRISPR IPSC and HSC HDR-editing approach for the study of other inherited monogenic disorders that result in immunodeficiency and/or immunodysregulation.   

Finally, in collaboration with Drs. Alice Bertaina and Paul Grimm, we have been involved in translational and clinical studies in which children with SIOD have received sequential  hematopoietic stem cell and a kidney transplant from the same parent. This “haplo/haplo” transplantation approach results in long-term tolerance of the kidney allografts by the immune system, allowing the discontinuation of all immunosuppressive medications. These studies have also confirmed the importance of the SMARCAL1 protein in maintaining the telomere length of HSCs and their blood-cell derivatives. We are interested in defining the importance of short telomeres in other features of the SIOD disease phenotype and in how SMARCAL1 deficiency results in short telomere length. 

Dr. Lewis and team are conducting a research study using an online registry for patients and their families to gather more information on the rare and complex disease of SIOD.  If you would like to join this registry, please complete the interest form below or reach out to Kristi Barnes at kbbarnes@stanford.edu and we will connect with you.