A Rice University lab won a prestigious National Institutes of Health grant to pursue gene-editing research that they hope will help lead to a cure for sickle cell disease (SCD). A four-year R01 grant to Gang Bao, Rice’s Foyt Family Professor of Bioengineering and a professor of chemistry and of materials science and nanoengineering. The $2.45 million grant will be administered by the National Heart, Lung, and Blood Institute.
Sickle cell disease impacts about 100,000 Americans and millions worldwide. A painful inherited and often fatal condition, the disease involves a single mutation in hemoglobin subunit beta (aka beta-globin) that forces normal, disc-shaped red blood cells to stiffen and take characteristic “sickle” shapes. These cells can damage vessel walls and clot small blood vessels, stopping the delivery of oxygen to the tissues.
The Grant will facilitate a Brown School of Engineering study of the outcomes of a CRISPR-Cas9 based editing of the beta-globin gene in hematopoietic stem/progenitor cells (HSPC) from patients with SCD, including the use of next-generation sequencing tools to quantify chromosomal rearrangements and assess the risk of inducing beta thalassemia in patients.
Context Into the Existing Research
Of the major projects underway in his lab, a cure for sickle cell disease has been a top priority for years. Recently, a study revealed CRISPR-Cas9 based editing of HSPC cells from patients with SCD has the ability to repair them, so cells differentiated from them display no signs of the disease phenotype. However, not all HSPCs could have the sickle mutation corrected; some showed cuts by Cas9 but no replacement of the mutant sequence, and others had no edits at all.
To date, about 25% of the HSPCs from patients were gene-corrected with donor DNA inserted into the genome. Professor Bao notes, “But there’s no integration of donor DNA in around 45% of cells that show cutting, and there’s always a fraction that has no cutting.” He has found that blood cells from HSPCs with cutting only showed an increased level of fetal hemoglobin, which is beneficial to patients. But the mechanisms of such phenomena remains elusive.
Some Outstanding Issues to Investigate
The team wants to also ensure that CRISPR-Cas9 editing would not lead to beta thalassemia, a blood disorder that reduces the production of hemoglobin. Professor Bao reports that the team needs to address key issues associated with Cas9 cutting (mechanism of inducing feta hemoglobin, chromosomal rearrangements, and the possibility of causing beta thalassemia) before applying for an FDA regulated clinical trial.
About Houston Rice University
Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences, and Social Sciences and is home to the Baker Institute for Public Policy. With 3,962 undergraduates and 3,027 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 4 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.
Gang Bao, Rice’s Foyt Family Professor of Bioengineering and a professor of chemistry and of materials science and nanoengineering