Adopting DNA editing for the management of immunodeficiency syndromes

Prof. Polina Stepensky, M.D.

Primary immunodeficiency (PID) syndromes are genetic disorders in which part of the body’s immune system is missing or does not function normally. It is estimated that one in 500 people in the United States alone are born with PID. Since one of the most important functions of a normal immune system is to protect against infection, the most predominant clinical consequence of PID is an increased frequency and unusually serious infections leading to severe morbidity and mortality. A primary treatment for PID is hemapoietic stem cell transplantation (HSC) derived from the bone marrow which can help replace the failing immune system. However, this treatment may come with severe side effects including an incomplete reconstitution of the patient’s malfunctioning immune response, infections related to delayed, or abnormal immune reconstitution; and secondary cancers.

Prof. Polina Stepensky, Chairman, Dept. of Bone Marrow Transplantation and Cancer Immunotherapy at Hadassah’s Medical Organization, treats in her ward a large number of PID patients, many of whom developed this disease with unknown genetic reason. These patients had been referred for DNA sequencing in the Dept. of Human Genetics which revealed novel mutations in critical immune genes. Prof. Stepensky’s research objective is focused on deciphering the cause-effect determining factor in such patients.

Prof. Stepensky and research team is presently working on using a novel technique called CRISPR-Cas9. This system is transforming genomic engineering and allows scientists with the ability to precisely and safely correct defective genes causing inherited diseases. CRISPR-Cas9 is a gene editing tool that could be termed as ‘molecular scissors’ to efficiently snip genetic mutations or defects at precise locations. Prof. Stepensky has successfully used cell cultures with this new method and plans to progress into an animal model of PID in the very near future. Her fervent objective is to use CRISPR-Cas9 to edit the DNA of HSC from PID patients or healthy donors in order to optimize the ability to reconstitute a failing immune system while reducing the adverse side effects associated with the transplantation procedure.

Prof. Stepensky has published extensively in peer-reviewed journals and collaborates with research teams around the world. She has identified previously unknown mutations that cause various immunological deficiencies in children and threaten their lives and has been awarded prestigious research grants from the European Union which funds and supports groundbreaking research grants.