A multi-institutional research team in Seattle recently was awarded more than $3.7 million in federal grant funding to develop a novel gene therapy approach for dangerous genetic disorders that affect hemoglobin, the blood’s oxygen-carrying molecules.
The most well-known of these disorders is sickle cell disease, a major cause of death in young children in many African nations. There is no curative therapy for these disorders short of a tissue-type-matched bone marrow transplant, which carries its own serious risks and is out of reach for most.
This four-year grant from the National Heart, Lung, and Blood Institute is co-led by two experts in the emerging field of gene therapy: Dr. Hans-Peter Kiem of Fred Hutchinson Cancer Research Center and Dr. Andrew Scharenberg of Seattle Children’s Hospital.
One reason this project is exciting, Kiem said, is that it holds promise for huge numbers of people.
“Approximately 300,000 children are born with sickle cell disease every year worldwide and there are about 100,000 affected patients in the United States ― a large patient population that could benefit from this treatment,” said Kiem, the Fred Hutch Endowed Chair for Cell and Gene Therapy.
This project aims to use a type of gene editing called CRISPR to modify the DNA regulatory sequence that turns down the production of fetal hemoglobin, a variant of the oxygen-carrying molecule that is found at high levels in fetuses and newborns but at low levels in most adults. Research has shown that people with sickle cell disease who happen to have unusually elevated levels of fetal hemoglobin have much milder sickle cell symptoms than other people with the disease. This approach to boost the production of fetal hemoglobin, the researchers hope, will make up for the inborn problems in the adult form of hemoglobin.
“What we would like to do is take patients’ own bone marrow and modify it in a way that it would be therapeutic when we put it back into the patients,” said staff scientist Dr. Olivier Humbert, who is managing the project for the Kiem Lab.
A unique aspect of the project is this focus on the blood stem cells of the marrow, the researchers said.
“There is not much experience there [in the field] with CRISPR in hematopoietic stem cells, and we’re probably one of the first ones exploring this,” Kiem said. Making the genetic modification at the blood stem-cell level, rather than in mature cells, would ensure a continual supply of blood cells with amped-up abilities to produce fetal hemoglobin, as older blood cells die and new ones develop to replace them.
The trial also incorporates a strategy the Kiem Lab developed for boosting the numbers of cells that have a gene modification: A specially engineered genetic sequence to give the modified cells a selective advantage after transplantation. This can help the researchers make sure that there are enough of the modified cells producing high levels of fetal hemoglobin to ameliorate the symptoms of the underlying disease.
The CRISPR tools for making the gene modification are currently being created and tested. The first tests in preclinical models should begin in a few months, Humbert said. The team hopes to launch a clinical trial in humans in several years, he said.
Susan Keown is an associate editor at Fred Hutchinson Cancer Research Center. She has written about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at email@example.com or on Twitter @sejkeown.