Genetic Engineering Publications - GEG Tech top picks

Gene therapy that alters hemoglobin genes may be an answer to curing sickle cell disease (SCD) and beta thalassemia. These two common life-threatening anemias afflict millions of individuals across the globe. Scientists at St. Jude Children's Research Hospital and the Broad Institute of MIT and Harvard used a next-generation genome editing technology, adenosine base editing, to restart fetal hemoglobin expression in SCD patient cells. The approach raised the expression of fetal hemoglobin to higher, more stable, and more uniform levels than other genome editing technologies that use CRISPR/Cas9 nuclease in human hematopoietic stem cells. The findings were published in Nature Genetics. 

The thickening of the heart muscle associated with hypertrophic cardiomyopathy leads to arrhythmia, heart failure and sudden cardiac death. The disease often goes undiagnosed, and heart transplantation is the only known treatment. Researchers have been working on a therapy using base editing to correct one of the mutations causing HCM. In this latest study, their target was a mutation in the myosin heavy chain 7 (MYH7) gene. MYH7 encodes β-myosin heavy chain, a motor ATPase that incorporates into heart muscle filaments and affects their contractions. Moreover, the pathogenic G-to-A mutation in the MYH7 gene studied is responsible for a severe, early-onset form of Crohn's disease. The team used the CRISPR-Cas 9 system to correct the MYH7 mutation in induced pluripotent stem cells derived from MHC patients, achieving extremely high editing efficiencies of up to 99%, with little or no off-target. The next step will be to obtain more data in a large animal model and make this potential therapy as safe as possible. 

Three young patients with relapsing T-cell leukemia have now been treated with CAR T cells. Data from the clinical trial show how the donor CAR T cells were engineered using cutting-edge gene-editing technology to modify single letters of their DNA code so that they could fight leukemia. To generate "universal" anti-T CAR T cell banks for the study, the researchers used T cells from healthy donors. They then made modifications to the cells using basic editing. The steps were: the deletion of existing receptors so that a donor's T cells could be banked and used without pairing, making them "universal", the deletion of a "flag" called CD7 so that T cells would not kill each other, the deletion of a second "flag" called CD52 to make the edited cells invisible to some of the potent drugs administered to the patient during the treatment process, and the addition of a chimeric antigen receptor that recognizes the CD7 T-cell receptor on leukemic T-cells to combat T-cell leukemia. The clinical trial for this treatment is still open and aims to recruit up to 10 patients. The teams hope that the treatment can be offered earlier in the treatment pathway. With additional funding, they also hope to make it available for adults in the future. 

The rare and fatal genetic disease CD3 delta severe combined immunodeficiency, also known as CD3 delta SCID, is caused by a mutation in the CD3D gene, which prevents the production of the CD3 delta protein needed for normal T cell development from blood stem cells. Currently, bone marrow transplantation is the only treatment available, but the procedure carries significant risks. In a study published in Cell, researchers showed that a new genome editing technique called base editing can correct the mutation that causes CD3 delta SCID in blood stem cells and restore their ability to produce T cells. The basic editor corrected an average of nearly 71 percent of the patient's stem cells in three experiments. The researchers then tested whether the corrected cells could give rise to T cells. When the corrected blood stem cells were introduced into artificial thymic organoids, they produced fully functional and mature T cells. The corrected cells remained four months after transplantation, indicating that the basic editing had corrected the mutation in the true self-renewing blood stem cells. The results suggest that the corrected blood stem cells could persist over the long term and produce the T cells that patients would need to lead healthy lives.