Shifting the PARADIGM to cure rare genetic hematological disorders.
PARADIGM is a new St. Jude initiative dedicated to advancing gene editing cures for rare genetic bone marrow failure disorders. The goal is to establish a scalable platform to create bespoke gene editing therapies for patients whose disorders are otherwise incurable.
PARADIGM aims to create a system capable of finding best-in-class gene editors for specific mutation classes in hematopoietic stem cells (HSCs). To that end, the project will innovate and implement high-throughput advanced liquid handling systems for massively parallel screening to identify the most useful gene editors and the best targets to pursue in follow-up screening. In addition, the project will incorporate machine learning to accelerate discovery and address the generated data’s large volume, including assessing the on-target and genome-wide activity of lead therapeutic editors.
Scientists in the St. Jude Department of Hematology will lead the effort and already have extensive experience to leverage into PARADIGM. They have previously modified HSCs, including using Cas9 nucleases, base editing and prime editing to treat or cure sickle cell disease. To monitor safety and off-target cutting, the researchers have created the genome-wide, unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) system, a safety effort that will be adapted into this new context. In addition, the institution maintains the St. Jude Bone Marrow Failure program, actively treating patients and learning about the genetic underpinnings of disease, such as SAMD9L/SAMD9L, GATA2 and RPA1 mutations, providing vital clinical and fundamental research expertise to push PARADIGM forward.
Over the next five years, PARADIGM will build on the foundational expertise at St. Jude to create a high-throughput platform for discovering and assessing individualized gene editing technologies to cure genetic bone marrow failure disorders.
