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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.
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Mitchell Weiss, MD, PhD
Member, St. Jude Faculty
Chair, Hematology Department
Arthur Nienhuis Endowed Chair in Hematology
Mitchell Weiss, MD, PhD
Member, St. Jude Faculty
Chair, Hematology Department
Arthur Nienhuis Endowed Chair in Hematology
Affiliations
Research Interests
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Mitchell Weiss, MD, PhD
Hematology
MS 800, Room D3022D
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678
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Shengdar Tsai, PhD
Associate Member, St. Jude Faculty
Shengdar Tsai, PhD
Associate Member, St. Jude Faculty
Affiliations
Research Interests
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Shengdar Tsai, PhD
Experimental Hematology
MS 355, Room D3022B
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38195-3678
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Marcin Wlodarski, MD, PhD
Associate Member, St. Jude Faculty
Marcin Wlodarski, MD, PhD
Associate Member, St. Jude Faculty
Affiliations
Research Interests
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Marcin Wlodarski, MD, PhD
Experimental Hematology
MS 341, Room D3007F
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678
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Senthil Bhoopalan, MBBS, PhD, FAA
Assistant Member, St. Jude Faculty
Senthil Bhoopalan, MBBS, PhD, FAA
Assistant Member, St. Jude Faculty
Research Interests
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Senthil Bhoopalan, MBBS, PhD, FAA
Bone Marrow Transplantation and Cellular Therapy
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, TN 38105-3678