Genetic Disorders

Sickle Cell Disease

Fred Hutch scientists are using precise gene-cutting tools such as CRISPR to develop gene therapies for sickle cell disease, which afflicts 100,000 Americans, mostly of African descent. An inherited gene mutation causes some of their red blood cells to have a crescent, or sickle, shape. Such cells can cling to one another, forming blockages that trigger episodes of extreme pain. These mutant red blood cells also die early, making the person anemic. Our research focuses on removing and replacing the gene responsible for the sickle cell trait with one that forms normal red blood cells. 

Using Structural Biology to Treat Genetic Disease

Fred Hutch scientists use X-ray crystallography to determine the three-dimensional shape of proteins. Our researchers have determined the structures of proteins called TAL effectors and meganucleases. Each of these can be used (alone or in combination) to guide gene-cutting enzymes to specific sections of DNA in mutant genes and disable them. One type of engineered protein, called a megaTAL, is being studied for use in a technique known as gene correction to moderate the effects of genes responsible for inherited disorders such as cystic fibrosis and sickle cell disease.

Finding the Genetic Links to Muscular Dystrophy

For decades, scientists struggled to understand the link between muscular dystrophy and flawed genes. Our researchers led the effort that identified a pair of genetic changes that are responsible for fascioscapulohumeral dystrophy (FSHD), the third most common form of the disease. Implicated was a gene that is normally active only in the development of an embryo.

Since then, our scientists have zeroed in on why this gene reactivates in people with FSHD, progressively destroying muscle cells. They discovered a group of proteins that work like a switch to shut off the gene early in life, and then they discovered another protein that blocks that switch. If they can find a drug to block the blocker, it could lead to a treatment for the disease. 

Gene Therapy in a Box, or Inside a Patient

Identifying mutant genes is just a first step in finding cures for genetic diseases or cancers. The next step is finding an efficient way to repair and reinstall them in the patient. Viruses can transport repaired genes. This typically involves removing living cells from a patient, infecting those cells with viruses bearing the repair gene in labs costing millions of dollars, and infusing the repaired cells into the patient.

Our scientists are pioneering a new approach that automates the gene engineering process in a device about the size of a microwave. It’s called “gene therapy in a box,” and it has the potential to make the process cheaper and available to many more people.

Our researchers are also looking for ways to deliver gene therapy directly to the patient, without the time and expense of removing cells and sending them to an outside lab. This has prompted searches for gene-carrying viruses that can safely transport and deposit the repaired genes. This method is called direct injection gene therapy. A family of microbes called foamy viruses has shown promise, but more testing is needed before it can be tried in humans.