Our researchers know that discoveries about the genetics of cancer can inform our understanding of genetic diseases that are not cancer, and vice versa. As our physician-scientists gain expertise in genetically engineering blood cells to fight malignancies, their work can be applied to gene therapies for other types of inherited diseases. The work is complementary, and our scientists remain driven by a shared goal: to eliminate these maladies as causes of human suffering and death.
Sickle cell disease (SCD) is a group of inherited red blood cell disorders. Red blood cells contain hemoglobin, a protein that carries oxygen. Healthy red blood cells are round and move through small blood vessels to carry oxygen to all parts of the body. In SCD red blood cells are crescent or sickle shaped and do not do not bend or move easily blocking blood flow to the rest of your body.
Down syndrome is a genetic disorder caused when abnormal cell division results in extra genetic material from chromosome 21. Typically, a baby is born with 46 chromosomes. Babies with Down syndrome have an extra copy of one of these chromosomes, chromosome 21. A medical term for having an extra copy of a chromosome is 'trisomy. ' Down syndrome is also referred to as Trisomy 21.
Dyskeratosis congenita (DC) is a rare, genetic form of bone marrow failure caused by a change (mutation) in a gene. Most often, the abnormal gene is passed to children by their parents (inherited). It can affect different organs, including the skin, finger nails and lungs. It is estimated that one out of one million people has this condition.
Fanconi anemia is a rare genetic disorder, in the category of inherited bone marrow failure syndromes. Half the patients are diagnosed prior to age 10, while about 10% are diagnosed as adults. Most people who have the disorder are diagnosed between the ages of 2 and 15 years. The disorder is often associated with a progressive deficiency of all bone marrow production of blood cells, red blood cells, white blood cells, and platelets.
Severe combined immunodeficiency (SCID) is a group of rare disorders caused by mutations in different genes involved in the development and function of infection-fighting immune cells. Infants with SCID appear healthy at birth but are highly susceptible to severe infections.
X-linked severe combined immunodeficiency (X-SCID) is a severe, genetic condition of the immune system. Signs and symptoms often become apparent in early infancy. X-SCID is caused by genetic changes in the IL2RG gene and is inherited in an X-linked recessive manner; it only affects males.
Our expertise in cancer genetics and blood stem cell transplantation informs our research into numerous inherited nonmalignant diseases that affect millions of people around the world. New, more precise DNA editing tools, such as CRISPR-Cas9, are boosting the prospects for curing such diseases with gene therapy.
Our research on genetic diseases cuts across many disciplines, involving fields as diverse as oncology, structural biology, virology and genome sciences. Our work extends to nonmalignant blood disorders such as sickle cell disease and beta thalassemia and inherited musculoskeletal diseases such as muscular dystrophy and cystic fibrosis. Our research interests include autoimmune diseases such as multiple sclerosis, which while not directly inherited, is associated with certain heritable genes that are known to increase the risk of developing it.
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.
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.
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.
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.