Genetic Therapies

Also known as Gene Transfer, Genome Editing, Gene Addition

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Overview

Genetic therapies aim to treat or cure conditions by correcting problems in your DNA. Your DNA, including specific genes, contains instructions for making proteins that are essential for good health. mutations, or changes in your DNA, can lead to proteins that do not work properly or that are missing altogether. These changes can cause genetics disorders such as cystic fibrosis, alpha-1 antitrypsin deficiency, thalassemia, hemophilia, and sickle cell disease.

Genetic therapies are approaches that treat genetic disorders by providing new DNA to certain cells or correcting the DNA. Gene transfer approaches, also called gene addition, restore the missing function of a faulty or missing gene by adding a new gene to affected cells. The new gene may be a normal version of the faulty gene or a different gene that bypasses the problem and improves the way the cell works.

Genome editing is a newer approach that allows precise correction or other targeted changes to the DNA in cells to restore a cell’s function. Genome editing can do the following:

Remove a stretch of DNA that causes a disease
Turn off a gene to prevent it from making a harmful protein
Turn on a gene or instruct a cell to make more of a needed protein
Correct a mutated gene

Gene transfer or genome editing treatments can directly modify the cells in your body, or your cells can be collected and treated outside of your body and then returned to you. For example, a doctor can remove immune system cells or bone marrow cells from your body, modify their DNA, and then re-introduce the cells to your body.

The only genetic therapies that are currently approved by the U.S. Food and Drug Administration (FDA) are for a rare inherited eye condition, as well as certain types of cancer. Genetic therapies that are in development could treat or cure other inherited disorders; treat other cancers; or treat infections, including HIV.

Explore this Health Topic to learn more about genetic therapies, our role in research and clinical trials to improve health, and where to find more information.

How It Works - Genetic Therapies

Genetic therapies may use gene transfer or genome editing approaches to change the DNA in a patient’s cells to treat a condition.

Gene transfer
- Genetic Therapies

Gene transfer introduces an additional gene into specific cells. This gene may stay as an extra piece of DNA in the cell or be inserted into the cell’s own chromosomes and thus become part of the cell’s own DNA.

A molecular package called a vector carries the gene to the cell nucleus, which is the central part of the cell where DNA is packaged in chromosomes. Vectors are created in the laboratory, often from viruses that have been modified to remove viral genes that cause disease and to carry a treatment gene.

Once the gene is inside the nucleus, the cell will start to make the critical protein needed for the cell to work properly. The new proteins make up for missing or faulty proteins and are meant to improve health for people who receive genetic therapies.

Illustration of gene transfer — **Gene transfer.** These two panels represent a cell with a faulty gene, caused by a mutation, before and after successful gene transfer. The faulty gene in this example makes proteins that are faulty, as shown at left. After gene transfer, the cell makes normal functional proteins from the addition of the treatment gene. Medical Illustration Copyright © 2019 Nucleus Medical Media, All rights reserved.

Genome editing
- Genetic Therapies

Genome editing introduces components that function together into cells. One component is a protein that cuts DNA, similar to a pair of molecular scissors. Another component is a guide molecule that can stick to DNA at specific sites. When the guide molecule sticks to an area of faulty DNA, the scissors protein attaches to the guide molecule, and cuts out the faulty DNA.

After the target DNA is cut, several things can happen. The cell may leave behind a gap, return the DNA to its original state, or fill in this gap with the corrected DNA. The cell can fill in the corrected DNA if it has a template DNA to direct the cell to rebuild a healthier version of the DNA that was removed. Therefore, sometimes a small piece of template DNA is introduced as a third component. This DNA is a corrected version of the faulty DNA, and it is used to rebuild the DNA correctly after it is cut open.

Illustration of genome editing — **Genome editing.** These two panels represent a cell with a faulty gene before and after successful genome editing. In this case, genome editing repairs the gene itself, rather than adding an extra gene. After genome editing, the repaired gene allows the cell to make normal functional proteins. Medical Illustration Copyright © 2019 Nucleus Medical Media, All rights reserved.

Who May Benefit - Genetic Therapies

In the future, genetic therapies may be used to prevent, treat, or cure certain inherited disorders, such as cystic fibrosis, alpha-1 antitrypsin deficiency, hemophilia, beta thalassemia, and sickle cell disease. They also may be used to treat cancers or infections, including HIV.

Genetic therapies that are currently approved by the FDA are available for people who have Leber congenital amaurosis, a rare inherited condition that leads to blindness. CAR T-cell therapy is FDA approved for people who have blood cancers, such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma.

What to Expect During Treatment - Genetic Therapies

Genetic therapies are still in the early stages of research, development, and clinical trials, but researchers already know a lot about how they may work as a treatment. For example, if you participate in a clinical trial or receive genetic therapy in the future, treatment may be provided in one of two ways. Your cells may be directly modified inside your body, or your cells may be collected and modified outside your body and then returned to you. The method may depend on your condition and what organ or types of cells in your body need to be treated.

Treatments for blood and immune conditions
- Genetic Therapies

If you have a blood or immune condition, the doctor may take blood from your veins or bone marrow from your hip bone to be modified in a laboratory with genetic therapy. Blood and bone marrow contain hematopoietic stem cells, which produce other key cells that make up the blood and immune system.

In the laboratory, scientists may use either gene transfer or genome editing to change the sample of stem cells provided by you. The modified cells are returned to your body through an intravenous (IV) line in one of your blood vessels. This procedure is called cell-based therapy or a blood and bone marrow transplant. The altered hematopoietic stem cells will produce healthy blood or immune cells.

Illustration of cell-based genetic therapy — **Cell-based genetic therapy.** The image shows how doctors take a patient’s hematopoietic stem cells to modify with genetic approaches in the laboratory. After the cells are modified, they go back into the patient’s body through a blood and bone marrow transplant. Medical Illustration Copyright © 2019 Nucleus Medical Media, All rights reserved.

Genetic therapies for sickle cell disease are examples of how this approach is being developed. Currently, a blood and bone marrow transplant of stem cells from a relative or an unrelated well-matched donor can cure sickle cell disease, but many patients do not have a well-matched donor available. Genetic therapies that modify a person’s own hematopoietic stem cells may provide a cure for people who do not have a well-matched donor. Modified hematopoietic stem cells can be injected into the blood, then the cells travel in the bloodstream to the marrow spaces inside the bones. Once inside the bone marrow, the cells can produce healthy red blood cells that do not sickle. Watch the video below to learn more about how genome editing is being tested for sickle cell disease.

Treatments for organs or tissues
- Genetic Therapies

Sometimes, genetic therapies are needed to alter cells that cannot be easily removed from the patient for treatment in the laboratory. Researchers are still working on ways to deliver the genetic therapy for these conditions. The methods being studied include IV infusion into the bloodstream, injection directly into an organ, and other ways to directly deliver the therapy into the affected tissues.

One condition that could be treated this way is hemophilia B. Hemophilia is caused by a faulty gene that prevents production of a protein necessary to clot the blood after an injury. Genetic therapy that is being developed for Hemophilia B involves infusing a vector carrying the normal clotting factor gene into the bloodstream. The vector then reaches liver cells to produce the clotting factor needed for better health.

What Are the Risks? - Genetic Therapies

Genetic therapies hold promise to treat many diseases, but they are still new approaches to treatment and may have risks. Potential risks could include certain types of cancer, allergic reactions, or damage to organs or tissues if an injection is involved.

Recent advances have made genetic therapies much safer. Better safety has resulted in the FDA approving some gene transfer therapies for clinical use in the United States. There have been a few clinical studies on genome editing, but the approach is much newer than gene transfer. Researchers are still studying the risks.

The National Institutes of Health, which includes the NHLBI, does not perform or fund studies on genome editing targeting sperm, eggs, or embryos in humans. These changes would be passed on to the patient’s children and could have unanticipated effects.

Research for Your Health

The NHLBI is part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH)—the Nation’s biomedical research agency that makes important scientific discovery to improve health and save lives. We are committed to advancing science and translating discoveries, such as genetic therapy approaches, into clinical practice to promote the prevention and treatment of heart, lung, blood, and sleep disorders. Learn about the current and future NHLBI efforts to improve health through research and scientific discovery.

Improving health with current research
- Genetic Therapies

Learn about some of the ways we continue to translate current research into improved health for people using genetic therapies. Research on this topic is part of the NHLBI’s broader commitment to advancing blood disorders and blood safety scientific discovery.

Accelerating Cures for Patients Who Have Sickle Cell Disease. The Cure Sickle Cell Initiative is an NHLBI-led collaborative research effort to develop genetic therapies for patients who have sickle cell disease. The goal is to have these genetic therapies ready to safely use in clinical research in 5 to 10 years. The patient-focused Initiative brings together academic and private sector researchers, patients, providers, advocacy groups, and others as it supports research, education, and community engagement activities.
Supporting Safe Manufacturing of Cell-based Therapies. The NHLBI’s Production Assistance for Cellular Therapies (PACT) supports translational research on cellular and genetic therapies by increasing the capacity to manufacture cell products that follow cGMP (current Good Manufacturing Practices) regulations. PACT offers education and resources through its five cell processing facilities and a coordinating center that support activities such as safety testing, product shipment, and design of clinical testing protocols.
Addressing Issues in Blood and Marrow Transplantation. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) was established to conduct large multi-institutional clinical trials to understand possible treatment approaches in blood and marrow transplants. In the United States, nearly 21,000 patients receive blood or marrow transplants annually, mainly for rare blood disorders.
Supporting Development of Genome Editing Tools. The NHLBI is helping to manage The Somatic Cell Genome Editing Program, a program supported by the NIH Common fund that aims to develop quality tools to perform effective and safe genome editing in human patients. These research tools will be made widely available to the research community to reduce the time and cost required to develop new therapies.
Combining New Approaches for Genome Editing in Sickle Cell Disease. NHLBI-funded research used a new genome editing technique, called CRISPR-Cas9, to remove the sickle cell mutation in stem cells in the laboratory. The researchers then used a virus vector to add a corrective gene to the stem cells. In preliminary laboratory tests, the red blood cells derived from the corrected stem cells produced almost all normal hemoglobin and very little sickle hemoglobin. This genetic therapy approach may hold promise for sickle cell disease, but more research is needed. Visit Experimental gene-editing approach holds promise for curing sickle cell disease for more information.
Helping scientists prepare gene therapies for clinical trials. The NHLBI-supported National Gene Vector Biorepository (NGVB) is a national resource for scientists conducting genetic therapy research. It provides a publicly available repository of AAV- and lentiviral plasmids, archiving services for samples generated during pharmacology-toxicology studies, and testing services for vector copy number, replication competency, and insertion site analysis. NGVB also offers a searchable database containing detailed summaries of more than 50 preclinical gene therapy pharmacology-toxicology studies and additional educational resources.
Supporting scientists performing NHLBI-funded gene therapy research. Our Gene Therapy Resource Program (GTRP) offers a variety of services to researchers to help them advance experimental gene therapies from the laboratory into clinical (human) trials. Since 2005, GTRP has provided safety testing services and set up a coordinating center to manage the program. GTRP can also help researchers apply for approvals from federal agencies to start clinical trials. These efforts have helped launch studies across a wide range of genetic, heart, lung, and blood diseases. Learn more about the GTRP and the projects it has supported.

Advancing research for improved health
- Genetic Therapies

In support of our mission, we are committed to advancing research on genetic therapies in part through the following ways.

We perform research. Our Division of Intramural Research, which includes investigators in our Hematology Branch and Sickle Cell Program, is actively engaged in research on genetic therapies. Researchers in NHLBI’s Cellular and Molecular Therapeutics Laboratory are pursuing strategies to correct the underlying mutation that causes sickle cell disease by using newly developed genome editing approaches.
We fund research. The research we fund today will help improve our future health. Our Division of Blood Diseases and Resources (DBDR) and Division of Cardiovascular Sciences oversee much of the research on genetic therapies we fund, helping us advance new genetic therapies for noncancerous blood disorders. The DBDR’s Gene Therapy Resource Program supports translational research on investigational genetic therapies to clinical testing by aiding the development of vectors, assisting with regulatory affairs, and funding genetic therapy clinical trials. Our Division of Lung Diseases also supports research that includes genetic therapies for inherited lung diseases such as cystic fibrosis. Search the NIH RePORTer to learn about research on genetic therapies that NHLBI is funding.
We stimulate high-impact research. Our Cure Sickle Cell Initiative is a patient-focused effort that engages investigators to develop genetic therapies for patients who have sickle cell disease. The NHLBI Strategic Vision highlights ways we may support research over the next decade, including new efforts for genetic therapies.

Learn about other exciting ways we are advancing research to improve lives.

Genetic therapies for alpha-1 antitrypsin (AAT) deficiency. The NHBLI continues to support research on the development of innovative methods to effectively deliver genetic therapy to treat the inherited lung disease, AAT deficiency. This work will build on previous work developing viral vectors that showed promise in earlier studies.
Genetic therapies for congestive heart failure. The NHLBI is supporting research into genes that may be useful for treating congestive heart failure and heart disease through gene transfer approaches. Some of this research aims to identify genes that might be ready to start testing for genetic therapy approaches.
Genetic therapies for cystic fibrosis. The NHLBI is supporting research on new genetic therapies to treat cystic fibrosis. New gene transfer virus vectors are being studied that may be better at delivering a corrected gene to lung cells. Researchers are also working on better methods to improve their genetic therapies in the laboratory before moving to clinical trials. Other research has shown success with genome editing that can fix the mutation in the gene that leads to cystic fibrosis using unique vectors that are not viruses. Researchers hope to improve these methods to use in clinical trials. Visit Genome editing for cystic fibrosis: A Q&A with Peter Glazer, Ph.D., M.D., for more information.
Genetic therapies for hemophilia. An NHLBI-supported study is testing the safety and success rate of genetic therapies in people who have hemophilia B. An early study showed promise, finding that almost half of the men who received genetic therapy could stop their regular treatment with clotting factor replacement therapy.
Improving genetic therapy approaches. Gene transfer into stem cells in bone marrow transplants is often not as successful as expected, so the NHLBI is supporting research into improving vectors and transplant techniques in the laboratory. The NHLBI is also funding research that will test new vectors for unique genome editing approaches for treating a range of diseases.

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Participate in NHLBI Clinical Trials

We lead or sponsor many studies relevant to genetic therapies using gene transfer or genome editing. See whether you or someone you know is eligible to participate in our clinical trials.

Do you or a child you know have lymphoma?

This study is testing a genetic therapy to prevent lymphoma from recurring. Participants in this study must be at least 3 years old and at high risk for recurrent lymphoma as determined by your doctor. This study is located in Chapel Hill, North Carolina.

View more information about Administration of T Lymphocytes for Prevention of Relapse of Lymphomas.

Do you know a newborn or toddler who has severe combined immunodeficiency?

This study will test the safety and effectiveness of genetic therapies to treat X-linked severe combined immunodeficiency (SCID-X1), a rare genetic immune disorder. The therapies could be a new approach to treat SCID-X1 in people who do not have a brother or sister to be a donor for stem cell transplant. To participate in this study, the child must be 2 years old or younger. This study is located in Memphis, Tennessee; San Francisco, California; and Seattle, Washington.

View more information about Gene Transfer for X-Linked Severe Combined Immunodeficiency in Newly Diagnosed Infants.

Are you an adult who has kidney cancer?

This study will test how a new genetic therapy approach works for patients who have kidney cancer. A patient’s white blood cells will be modified in the laboratory using genetic therapies. Patients will receive different doses of their own, modified white blood cells. To participate in this study, you must be between 18 and 70 years old and have a diagnosis of progressive renal cell carcinoma. This study is located in Bethesda, Maryland.

View more information about HERV-E TCR Transduced Autologous T Cells in People with Metastatic Clear Cell Renal Cell Carcinoma.

Learn more about participating in a clinical trial.

View all trials from ClinicalTrials.gov.

More Information

After reading our Genetic Therapies Health Topic, you may be interested in additional information found in the following resources.

NHLBI resources
- Genetic Therapies

Non-NHLBI resources
- Genetic Therapies

Cystic Fibrosis (National Library of Medicine [NLM], MedlinePlus)
Genes and Gene Therapy (NLM, MedlinePlus)
Genetics 101 (NLM, MedlinePlus)
Hemophilia (NLM, MedlinePlus)
Learning About Cystic Fibrosis (National Human Genome Research Institute)
Sickle Cell Disease: What You Should Know (NLM, MedlinePlus)
What Is Gene Therapy? How Does It Work? (U.S. Food and Drug Administration)

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Genetic Therapies