Genetic Disorders

Broken, missing or mutated genes are root causes of most cancers. Decades of cancer research at Fred Hutch have given our scientists a deep understanding of other diseases — unrelated to cancer — that are also the result of genetic flaws. Our research expertise therefore includes a long list of diseases thought to have genetic links, including muscular dystrophy, sickle cell disease, cystic fibrosis, Fanconi anemia and multiple sclerosis. Like some cancers, these diseases are often passed down in families, sometimes skipping many generations.

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.
 

Endogenous expression of the DUX4 transcription factor in cultured facioscapulohumeral muscular dystrophy (FSHD) muscle cells.
Endogenous expression of the DUX4 transcription factor in cultured facioscapulohumeral muscular dystrophy (FSHD) muscle cells. Dr. Stephen Tapscott / Fred Hutch

Genetic Disorders Research

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. 

Sickle Cell Disease

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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

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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

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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

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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.

Selected Genetic Disorder Clinical Trials

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Our Genetic Disorder Researchers

Our interdisciplinary scientists and clinicians work together to prevent, diagnose and treat genetic disorders as well as other cancers and diseases.

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A Patient’s Story

Andrew Adams

Andrew Adams

From birth, Andrew Adams experienced bouts of severe abdominal pain, high fevers and mouth pain that made eating impossible. At age 9, his condition was traced to an extremely rare and life-threatening genetic disorder: trisomy 8 mosaicism, which caused his immune cells to attack healthy tissues. At age 18, he received a lifesaving transplant with bone marrow from his sister. He not only survived but finished high school and found a job he loves.

Last Modified, July 16, 2019