173 Gene Therapy and Death in 2000

Some diseases are caused by inherited mutations to genes. Of these diseases, some are caused by mutations of a single gene, like sickle cell disease. Scientists developed the technology called gene therapy to treat these types of diseases for ailing animals. Gene therapy aims to replace the defective mutated gene with an unmutated version of the gene. Because of the success in animals and with individual human cells in the labs, scientists were hoping to help humans by using gene therapy for a whole living, breathing human.

In 1999, an approved clinical trial was done to test the safety of gene therapy for a  disorder of nitrogen metabolism. The gene therapy was aiming to treat deficiency of the enzyme ornithine transcarbamylase. A virus containing the corrected version of the gene was used to treat 18 volunteers. 18-year-old Jesse Gelsinger suffered from a mild version of the disease and received the gene therapy. Four days after he received the gene therapy, he passed away. This tragic loss led to a lawsuit, a stop to gene therapy trials, and investigations, including one by a committee of the senate of the United States in Washington, DC. Gene therapy slowed down as a treatment option. Some ethical questions and other concerns were raised. The Food and Drug Administration created more regulations and review processes for clinical trials using gene therapy.  In 2009, scientific publications announced that gene therapy was again considered a valuable option (A Comeback for Gene Therapy. Luigi Naldini. Science. 6 Nov 2009).

Sickle cell disease (SCD) occurs in people who inherit two copies of the sickle cell gene, one from each parent. This produces abnormal hemoglobin, called hemoglobin S. (Hemoglobin is the protein molecule in red blood cells that carries oxygen from the lungs to the body’s tissues and returns carbon dioxide from the tissues to the lungs.) When an individual inherits one copy of the sickle cell gene from a parent, the person is said to have sickle cell trait (SCT). People with SCT usually do not have any of the symptoms of SCD and live a normal life.

Ethics questions

• Is it ethical that the scientist who is conducting the clinical trial also owns a company that is getting paid for participating in the clinical trial?
• Is it ethical to ask volunteers with the disease to participate in a phase 1 trial that studies only if a treatment doesn’t cause unnecessary harm instead of a phase 3 trial that studies if a treatment actually improves their condition?
• What is a better ethical choice involving babies in a clinical trial phase 1 that would die from severe cases of the disease without treatment in a year? Babies cannot understand the risks of the treatment. If the treatment can cause death, but if lack of treatment also causes death within 12 months? Is it better to involve adults who can make an informed decision and understand the risk? If adults have a mild form of the disease that can survive by sticking to a harsh diet without harm to their lives, but participation in a clinical trial phase 1 has a chance of causing life-ending harm, is that a better way to conduct a phase 1 clinical trial?
• Is it ethical to withhold information from the volunteer participant that some monkeys died after receiving gene therapy?

Further reading

US faces ethical issues after gene therapy death. (2000). BMJ: British Medical Journal, 320(7235), 602. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1173791/ accessed 4/6/2022

Savulescu J. Harm, ethics committees and the gene therapy death. Journal of Medical Ethics 2001;27:148-150. https://jme.bmj.com/content/27/3/148 or https://jme.bmj.com/content/medethics/27/3/148.full.pdf accessed 4/6/2022

Sibbald B. (2001). Death but one unintended consequence of gene-therapy trial. CMAJ: Canadian Medical Association journal = journal de l’Association medicale canadienne, 164(11), 1612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81135/ accessed 4/6/2022

Herzog, R. W., Cao, O., & Srivastava, A. (2010). Two decades of clinical gene therapy–success is finally mounting. Discovery medicine, 9(45), 105–111. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586794/ accessed 4/6/2022

Long Term Follow-Up After Administration of Human Gene Therapy Products. Food and Drug Administration. January 2020.  https://www.fda.gov/media/113768/download accessed 4/6/2022

A Comeback for Gene Therapy. Luigi Naldini. Science. 6 Nov 2009. Vol 326, Issue 5954. pp. 805-806  DOI: 10.1126/science.1181937 accessed 4/6/2022