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Genetic Therapy Definitions Somatic cell gene therapy: alteration of genes of a diseased individual, often only in a target organ or tissue. Germ-line gene therapy: alteration of germline cells of an individual, so that subsequent generations also are affected by the change. Techniques First somatic cell gene therapy procedures: – Inserted a normal gene into the DNA of cells in order to compensate for the nonfunctioning defective gene. – Involves obtaining blood cells from a person afflicted with a genetic disease and then introducing a normal gene into the defective cell. – The normal gene is delivered using a domesticated retrovirus that infects the cell, introducing the properly functioning gene. – Retroviruses can infect many types of cells, so it is important to develop gene transfer techniques that allow only retroviruses to deliver genes to a cell and then remain there. – Furthermore, the new gene must not get to the wrong place in the genome of the cell. – For cystic fibrosis: adenovirus used as vector – Other studies: new DNA introduced directly into skin cells or tumor cells Germ-line gene therapy: Technically more difficult and raises more ethical challenges Two main methods: – Treat a pre-embryo with a serious genetic defect before implantation in the mother (involves IVF) – Treat germ cells of affected adults Candidate Diseases for Gene Therapy Single gene defects more likely to respond 1993: gene therapy approved for: – – – – Severe combined immune deficiency (SCID) Familial hypercholesterolemia Cystic fibrosis Gaucher's disease More recently: – Most protocols aimed toward the treatment of cancer – A few also targeted toward AIDS Future: – – – – Parkinson's Alzheimer's disease Arthritis Heart disease Criteria for selection – The disease is an incurable, life-threatening disease – Organ, tissue and cell types affected by the disease have been identified – The normal counterpart of the defective gene has been isolated and cloned – The normal gene can be introduced into a substantial subfraction of the cells from the affected tissue – (or) introduction of the gene into the available target tissue, such as bone marrow, will somehow alter the disease process in the tissue affected by the disease – The gene can be expressed adequately (it will direct the production of enough normal protein to make a difference) – Techniques are available to verify the safety of the procedure Historical Notes on Gene Therapy First Attempt – Performed under questionable circumstances by University of California at Los Angeles (UCLA) Researcher: Dr. Martin Cline – Without the approval of his UCLA IRB, performed recombinant DNA transfer into cells of the bone marrow of two patients with hereditary blood disorders in Italy and Israel – At the time, Italy did not have IRBs, and Dr. Cline did not disclose fully details to the Israeli IRB Dr. Cline suffered grave consequences Forced to resign his department chairmanship at UCLA and lost some grants Response to Ethical Crisis: Called for ethical review: – – – National Council of Churches Synagogue Council of America United States Catholic Conference President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research vigorously defended the continuation of rDNA research Suggested that the Recombinant DNA Advisory Committee (RAC) to the NIH broaden the scope of its review to include the ethical and social implications of gene therapy Results of further research: September 14, 1990: researchers at the U.S. National Institutes of Health – Performed the first (approved) gene therapy procedure on four-year old Ashanti DeSilva – Born with a rare genetic disease: severe combined immune deficiency (SCID) – Children with this usually develop overwhelming infections and rarely survive to adulthood Common childhood illnesses like chickenpox life-threatening Ashanti led a cloistered existence Gene therapy procedure: – Doctors removed white blood cells from the child's body – Let the cells grow in the lab and inserted the missing gene into the cells – Infused the genetically modified blood cells back into the patient's bloodstream – Strengthened Ashanti's immune system: Results Ashanti no longer has recurrent colds allowed to attend school immunized against whooping cough not a cure: the white blood cells treated genetically only work for a few months, and the process must be repeated every few months Other Protocols 1990 – two other protocols – gene therapy on children like Ashanti DeSilva who suffer from SCID – tumor — infiltrating blood cells genetically altered to deliver tumor necrosis factor to tumor cells 1992 – Director of NIH, approved a compassionate use exemption: – allowed a critically ill patient to receive gene therapy – circumvention of the regular approval process proved very controversial Gene Therapy Tragedies 1999 – death of Jesse Gelsinger, the first fatality in a gene therapy experiment Subsequent investigations revealed that the deaths of six gene therapy patients United States Senate held hearings on this topic on February 2, 2000 Ethical Arguments - Pro Arguments in Favor of Gene Therapy – Central argument: can be used to treat desperately ill patients, or to prevent the onset of horrible illnesses. – Conventional treatment has failed for the candidate diseases for gene therapy, and for these patients, gene therapy is the only hope for a future. – Germ-line gene therapy offers a true cure, and not simply palliative or symptomatic treatment – Germ-line gene therapy may be the only effective way of addressing some genetic diseases Ethical Arguments - Pro (cont) – By preventing the transmission of disease genes, the expense and risk of somatic cell therapy for multiple generations is avoided – Medicine should respond to the reproductive health needs of prospective parents – The scientific community has a right to free inquiry, within the bounds of acceptable human research. Ethical Arguments - Pro (cont.) Solves later moral dilemmas about human embryos: Germ-line gene therapy techniques will undoubtedly place some embryos at risk But once the successful techniques are developed, "defective" embryos could be repaired. Eliminates need for their destruction Ethical Arguments – Con Arguments Against Gene Therapy – "Slippery slope" argument: Is it possible to distinguish between "good" and "bad" uses of gene modification techniques? Should the potential for harmful abuse of the technology keep us from developing more techniques? – The difficulty of follow-up Patients need to be under surveillance for decades to monitor long-term effects of the therapy on future generations – Many gene therapy candidates are children too young to understand the ramifications of gene therapy treatment. Ethical Arguments – Con (cont.) Conflict of interest problems: – Individual's reproductive liberties and privacy interests v. the interests of insurance companies – Justice and resource allocation: In a time of strain on our health care system, can we afford such expensive therapy? Who should receive gene therapy? If it is made available only to those who can afford it, "the distribution of desirable biological traits among different socioeconomic and ethnic groups would become badly skewed" Ethical Arguments – Con (cont.) Against germ-line gene therapy techniques: – Involve too much scientific uncertainty and clinical risks, and longterm effects of such therapy are unknown – Would open the door to attempts at altering human traits not associated with disease: could exacerbate problems of social discrimination – Involves research on early embryos and affects their offspring: essentially creates generations of unconsenting research subjects – Very expensive, and will never be cost effective enough to merit high social priority – Germ-line gene therapy would violate the rights of subsequent generations to inherit a genetic endowment that has not been intentionally modified.
