Gene therapy is permitted but must be approved by the Department of Health and Human Services (DHHS), which is responsible for overseeing clinical trials. The Food and Drug Administration (FDA), a DHHS agency, considers any use of CRISPR in humans to be a form of gene therapy. Germline gene therapy—editing of embryos that changes the germline—is regulated even more strictly.
Gene therapy is an experimental technique that uses genes to allow doctors to treat or prevent a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery. Examples include: (1) Replacing a mutated gene that causes disease with a healthy copy of the gene; (2) Inactivating, or “knocking out,” a mutated gene that is functioning improperly; (3) Introducing a new gene into the body to help fight a disease. One type of gene therapy is stem cell therapy, in which a patient’s own stem cells are used to repair or rebuild tissue.
Gene therapy products must go through an approval process coordinated by two DHHS agencies: the Office for Human Research Protections and the FDA through the Center for Biologics Evaluation and Research (CBER). CBER uses both the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act for oversight. In 2020, the FDA released a set of guidances to encourage the continued development of safe and effective gene therapies. Another DHHS agency, the National Institutes of Health (NIH), oversees federally-funded clinical trials and adds additional requirements for federally-funded trials to be approved.
Clinical studies of gene therapy in humans require the submission of an investigational new drug application (IND) prior to their initiation in the US, and marketing of a gene therapy product requires submission and approval of a biologics license application (BLA). There are more than 900 IND applications for gene and stem cell therapies in the pipeline. For the first time, doctors in the US used CRISPR gene editing to treat a patient with a genetic disorder—sickle cell disease—in 2019.
- Inherited blindness: FDA approved clinical trials for gene therapy using CRISPR to treat Leber’s congenital amaurosis type 10, the most common form of inherited blindness in children. The first clinical trial began in 2019 and the first patient was treated in 2020, making this the the world’s first human study of an in vivo, or inside the body, CRISPR gene editing medicine.
- Sickle cell: CRISPR used for the first time to treat patients with the genetic blood disorder. Another trial is underway for a similar blood disorder, beta-thalassemia. The first two patients have shown promising results from the treatment.
- Cancer: Multiple areas, including genetically engineered viruses (oncolytic viruses) that directly kill cancer cells, gene transfer to alter the abnormal functioning of cancer cells, blood cancers, lymphoma, certain types of leukemia, melanoma, inoperable melanoma, ALL, squamous cell cancer of the head and neck, liver, ovaries, prostate, bladder, and other organs, and immunotherapy, which includes CAR T-cell therapy for some children and adults with leukemia or lymphoma. In 2017, the FDA approved CAR T-cell therapy as standard treatment for children with acute lymphoblastic leukemia (ALL) and a second for adults with advanced lymphomas. A CAR T-cell therapy for a type of B-cell lymphoma showed promising results 3 years after treatment. In 2019, the FDA granted Fast Track status to a new immune cell therapy to treat solid tumors and lymphomas. Another trial, beginning in 2018, has treated three patients, two with multiple myeloma and one with sarcoma, with CAR T-cell therapy.
- Relapsed cancer: First clinical trial in the US to use CRISPR began in 2018 to treat multiple types of relapsed cancer. Three patients have begun treatment.
- Neuromuscular disease: FDA approved gene therapy treatment for spinal muscular atrophy, which in severe cases cause infants to die or rely on permanent breathing support by age 2.
- Inherited vision loss: FDA approved gene therapy to treat children and adult patients with inherited form of vision impairment that could result in blindness.
- Porphyria: FDA approved gene therapy to treat porphyria, a disease in which a build-up of toxic proteins cause severe pain, paralysis, and sometimes death.
- Fatal muscle disease: Clinical trials ongoing for gene therapy for X-linked myotubular myopathy, a muscle disease in which patients typically survive only into early childhood.
- Hunter syndrome: Clinical trials ongoing using a gene editing technique called ZFNs to treat Hunter syndrome, a disease in which the body cannot break down sugar molecules, which results in the buildup of compounds in internal organs and usually leads to death in the teenage years.
- HIV: Clinical trials underway using ZFNs to modify immune system cells to treat HIV.
- Hemophilia: Four clinical trials currently ongoing to edit the patient’s cells to allow the blood to clot normally.
- Hemophilia A: A license application was submitted to the FDA in 2019 for the first gene therapy to treat a hemophilia A, a blood clotting disorder, and is expected to receive FDA approval for marketing in 2020.
- Antibiotic: Locus Biosciences of Morrisville used CRISPR to develop a new type of antibiotic to attack bacteria resistant to other antibiotics. Clinical trials will begin in 2020.
- Neurodegenerative disorder: Weill Cornell Medical College researchers completed a study with mice showing that gene therapy could possibly treat chronic traumatic encephalopathy, a brain disorder caused by repetitive brain trauma.
- Muscular dystrophy: Pre-clinical trials in dogs and mice ongoing using CRISPR to treat Duchenne muscular dystrophy, in which patients typically die before age 30, usually from heart failure. A human clinical trial was halted in 2019 after a patient suffered severe side effects.
- Progeria: The Progeria Research Foundation (PRF) submitted final results to the FDA of clinical trials for a gene therapy to treat some symptoms and extend survival in children and teens with a type of progeria, a disease that causes rapid-aging and usually results in death during adolescence.
- Hyperlipidemia: Collaboration of Tufts University and Chinese Academy of Sciences leads to development of nanoparticle delivery system to carry CRISPR gene-editing tools into liver cells.
- Cancer vaccine: More than two dozen clinical trials are underway to test personalized vaccines for cancer.
- Rare form of blindness: Gene therapy for patients with a rare form of inherited blindness called biallelic RPE65 mutation-associated retinal dystrophy. FDA approved in 2017.
- Vein disease: Gene therapy to treat severe cases of veno-occlusive disease, a disorder in which the small veins of the liver become obstructed, in patients who have received a bone marrow transplant. Approved in 2017.
- High cholesterol: Gene therapy to lower LDL levels in patients who have dangerously high cholesterol. Approved in 2013.
- Improvements to CRISPR: In 2019, Harvard University researchers developed a variant of CRISPR that addresses some of its drawbacks.
- Kidney disease research: Mayo Clinic researchers studied a new type of gene therapy that can more effectively reach the kidney.
- Anti-aging research: In 2019, Harvard University researchers combined three gene therapies to treat obesity, type II diabetes, heart failure, and renal failure in mice.
- Common cold research: Gene editing in mice and human lung cells has been able to provide protection against the common cold and other viruses by modifying a gene that is required for the viruses to replicate.
- Obesity research: Salk Institute researchers manipulated genes in mice that enabled them to burn fat more efficiently and exercise almost twice as long as they could before, with the goal of developing a a safe, effective treatment for humans struggling with obesity.
Stem Cell Therapies
- ‘Bubble boy’ disease: Stem cell treatment developed by researchers at the National Institute of Allergy and Infectious Diseases to treat severe combined immunodeficiency, a disease of the immune system that causes everyday germs to be potentially fatal.
- Macular degeneration: Researchers at the University of Southern California used stem cell therapy to treat blindness caused by macular degeneration.
- Kidney transplant: Researchers are using stem cell therapy to help prevent organ rejection after a transplant. The final clinical trial is due to be completed in 2022.
- Diabetes: Researchers are using stem cells to replace cells in the pancreas that produce insulin. The current clinical trial is due to be completed in 2021.
- Parkinson’s disease: Researchers are using stem cells to reduce inflammation in the brain which is thought to contribute to Parkinson’s disease. One clinical trial has been completed.
2020: FDA releases guidances on gene therapy product development that encourage the development and approval of multiple treatments to create competitive drug markets and provide recommendations to help ensure new products meet the FDA’s standards for safety and effectiveness. The guidances also highlight the need for reliable post-market follow up, such as post-market clinical trials, to help ensure that treatments are safe and innovative.
2019: California passes a bill to making it illegal to sell a do-it-yourself genetic engineering kit unless it comes with a clear warning stating that “the kit is not for self-administration.” No kits are being sold at this time, but the bill is a proactive measure to regulate biohacking as CRISPR gene editing becomes more common.
2019: The U.S. Department of Health and Human Services does not renew a research contract with the University of California San Francisco involving human fetal tissue from elective abortions to develop testing protocols and announces measures to limit future research involving fetal tissue.
2017: The National Academy of Sciences releases report on guidelines for editing the human genome to treat diseases and other applications.
2017: FDA approves the first directly administered gene therapy, Luxturna, that targets a disease caused by mutations in a specific gene, to treat children and adults with inherited vision loss.
2017: FDA approves Kymriah (tisangenlecleucel) for patients up to 25-years of age with precursor to acute lymphoblastic leukemia (ALL).
2015: FDA approves Imlygic, a modified herpes virus used to infect and kill melanoma cells.
2012: FDA finalizes Breakthrough Therapy Designation, which expedites the development of drugs intended to treat conditions where preliminary evidence shows substantial improvement over existing therapies.
2009: President Barack Obama signs Executive Order (Removing Barriers to Responsible Scientific Research Involving Human Stem Cells), which allows for new embryonic stem cell research.
2001: President George W. Bush bans federal funding for research on new embryonic stem cell lines.
1996: Dickey-Wicker Amendment passes, which prevents federal funding of research involving the creation or destruction of human embryos.
1993: FDA declares gene therapies will be regulated as a drug, device or biologic product depending on the final product and its intended use.
1944: Public Health Service Act passes, which gives the DHHS authority to oversee health care technology.
1938: Federal Food, Drug, and Cosmetic Act passes, which gives the FDA authority to oversee drug safety.
- Genetic Literacy Project’s FAQ on gene editing
- FDA Continues Strong Support of Innovation in Development of Gene Therapy Products