NIH grant to find if scale of gene editing changes harmful or helpful

$2.6M award furthers work into large DNA alterations with CRISPR/Cas9 use

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Researchers at Rice University in Texas have been awarded $2.6 million to further investigate questions surrounding the safety and efficacy of gene editing as a potentially curative treatment for sickle cell disease (SCD).

The four-year grant from the National Institutes of Health (NIH) was awarded to Gang Bao, PhD, a bioengineer at Rice.

Following up on a discovery, led by Bao, that the gene editing technology called CRISPR/Cas9 leads to larger than expected modifications of genetic material, he and his team want to better understand the biological consequences of these changes, some of which might be helpful to SCD patients.

“We believe some of the large deletions actually could be beneficial,” Bao said in a university press release. “But we need to do more work to figure out which large deletions might achieve this and how to utilize them for curing sickle cell disease.”

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CRISPR/Cas9 gene editing for sickle cell could be harmful or beneficial

Gene editing is gaining traction as a treatment approach for diseases with a known genetic cause. Broadly, the strategy involves collecting stem cells from a patient and performing a one-time modification to DNA regions that are known to be implicated in disease, before returning the corrected cells to the patient.

SCD is caused by mutations in the beta-globin (HBB) gene, driving the formation of an abnormal version of hemoglobin — the protein that’s responsible for carrying oxygen throughout the body. Because the disease results from changes in a single gene, it is considered a prime candidate for gene editing therapies.

In addition to directly correcting mutations in HBB, gene editing can be used to turn on fetal hemoglobin production. This version of hemoglobin is produced in a fetus before birth; after a child’s birth, it’s switched off and replaced by adult hemoglobin, the version with the protein that’s faulty in SCD. Notably, fetal hemoglobin is more effective than its adult counterpart at transporting oxygen throughout the body.

Gene editing via CRISPR/Cas9 technology leverages a natural defense system that bacteria use against viruses.

Simply put, an enzyme called Cas9 is targeted to a particular DNA section by a guide molecule. The enzyme then cuts into the DNA, allowing for the genetic code there to be edited.

This system long was thought to only create small cuts in targeted DNA, taking out or putting in genetic segments no larger than 50 nucleotides, the building blocks of DNA.

But previous work by Bao’s team found considerably larger DNA alterations created by CRISPR-Cas9.

“We found that these modifications are in fact much larger — ranging from about 200 to several thousand nucleotides,” Bao said.

The team made this observation in cells from SCD patients using different types of guide molecules.

Large-scale changes to DNA could have consequences that make gene editing therapy less effective or safe, or they could make the therapy more effective.

Work into how DNA changes affect messenger RNA, proteins, and stem cells

With the NIH funding, the researchers want to figure out why these large modifications happen and investigate their downstream consequences.

“Now we have a good picture of what happens in terms of the DNA,” Bao said. “Next, we want to understand what happens at the level of messenger RNA and proteins.”

Messenger RNA, or mRNA, is an intermediate molecule that acts as a template for protein production, based on instructions found within a gene’s DNA. Changes in DNA can disrupt the formation of its RNA template, affecting protein production.

The scientists will look at how mRNA levels and protein structure might be altered by large DNA modifications, and if those changes influence the development and function of stem cells.

Bao and his team think there may be certain advantages to these larger-than-expected genetic alterations, like inducing “the expression of fetal hemoglobin, which would help cure sickle cell disease,” he said.

“We need to understand the major biological consequences of having these unintended large gene modifications and then figure out how to best address this problem,” Bao said.