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Sickle Cell: Progress In Research

By Rosaland Tyler

Associate Editor
New Journal and Guide

Researchers continue to develop new treatments for sickle cell anemia, a disease with no known cure.
Since National Sickle Cell Awareness Month ends in September, it is a great time to look at some of the cutting-edge treatments researchers have developed in the past few years for a disease that affects about 100,000 patients in the United States and strikes about 300,000 children at birth each year worldwide.
One example is the promising gene editing research Rice University bioengineer Gang Bao is conducting. This means since a single DNA mutation causes the body to make sticky, sickle-shaped red blood cells that contain abnormal hemoglobin and can block blood flow in limbs and organs.
Bao is conducting gene-editing research that aims to fix this mutation. During a February 2018 talk at the annual American Association for the Advancement of Science meeting in Austin, Bao said results from a series of tests showed CRISPR/Cas9-based editing could fix the mutation. His presentation was part of a scientific session titled, “Gene Editing and Human Identity: Promising Advances and Ethical Challenges.”
Bao explained his new research this way. “Sickle cell disease is caused by a single mutation in the beta-globin gene (in the stem cell’s DNA),” he said. “The idea is to correct that particular mutation, and then stem cells that have the correction would differentiate into normal blood cells, including red blood cells. Those will then be healthy blood cells.”

Specifically, researchers injected gene-edited cells into the bone marrow of immunodeficient mice and tested after 19 weeks to see how many retained the edit. “The rate of repair remained stable, which is great,” said Bao who is conducting the study with researchers at Baylor College of Medicine, Texas Children’s Hospital and Stanford University.

Another major finding of the study is that the CRISPR/Cas9 system could introduce large alterations to the genes in patients’ cells, in addition to small mutations or deletions. These off-target effects could cause a disease.

The findings, part of an upcoming paper, are a step toward treating sickle cell disease. Obstacles hindering a cure include optimizing the CRISPR/Cas9 system to eliminate off-target effects, as well as finding a way to increase the amount of gene-corrected stem cells.

Bao said researchers still don’t know whether repairing as much as 40 percent of the cells is enough to cure a patient. “We’d like to say, ‘Yes,’” he said, “but we don’t really know yet. That’s something we hope to learn from an eventual clinical trial.”

More research that is promising is surfacing in other studies including a pre-clinical study at Fred Hutchinson Cancer Research Center, which could lead to human trials. Researchers used CRISPR-Cas9 to edit long-lived blood stem cells to reverse the clinical symptoms observed with several blood disorders, including sickle cell disease and beta-thalassemia. The results were published in the July 31 issue of Science Translational Medicine.

Fred Hutch researchers used CRISPR-Cas9 gene editing to a remove a piece of genetic code that normally turns off fetal hemoglobin proteins. Snipping this control DNA with CRISPR enables red blood cells to continuously produce elevated levels of fetal hemoglobin.

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The edits were taken up efficiently by the targeted cells: 78 percent took up the edits in the lab dish before they were infused. Once infused, the edited cells settled in (“engrafted”), multiplied, and produced blood cells, 30 percent of which contained the edits. This resulted in up to 20 percent of red blood cells with fetal hemoglobin, the type of hemoglobin that reverses disease symptoms in sickle cell disease and thalassemia.

“Not only were we able to edit the cells efficiently, we also showed that they engraft efficiently at high levels, and this gives us great hope that we can translate this into an effective therapy for people,” said senior author Dr. Hans-Peter Kiem, director of the Stem Cell and Gene Therapy Program and a member of the Clinical Research Division at Fred Hutch.

“Targeting this portion of stem cells could potentially help millions of people with blood diseases,” said Kiem, who holds the Stephanus Family Endowed Chair for Cell and Gene Therapy.

Kiem said, “Twenty percent of red blood cells with fetal hemoglobin – what we saw with this method – would be close to a level sufficient to reverse symptoms of sickle cell disease.”

This was the first study to specifically edit a small population of blood cells that Kiem’s team identified in 2017 as solely responsible for regrowing the entire blood and immune system. His team distinguished this select group as CD90 cells, named for a protein marker that sets them apart from the rest of the blood stem cells (known by another protein marker, CD34).

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