1. GENE THERAPY
CHAPTER 9
BIOETHICS

2. Ethics Approved clinical trials of gene therapy target somatic cells.
Germline gene therapy has not been approved for ethical reasons.
Patient treated
Somatic Cells Repairs
Patient, their progeny and the gene pool altered.
Germline repairs

3. Perspective on Gene Therapy
Great promise, but slower than expected
More complex than expected
Gene interactions
Appropriate vectors
Adequately targeting and sustaining therapeutic effects
Safety issues

4. History of Gene Therapy Ethics
19th Century Biologist August Weismann establishes the “Weismann Barrier”
1974: NIH regulates recombinant DNA research. Recombinant DNA Advisory Committee (RAC) to the NIH Director was created.
1984: RAC creates new group, Human Gene Therapy Working Group (later called Human Gene Therapy Subcommittee, or HGTS)
1984: U.S. Office of Technology Assessment (OTA) publishes background paper Human Gene Therapy
1985: RAC Subcommittee prepares “Points to Consider” document for public presentation
1992: NIH Director Dr. Bernadine Healy approves compassionate use exemption of gene therapy for critically ill patient
1998: HUGO Ethics Committee makes statement on gene therapy ethics.
1999: first death by gene therapy, Jesse Gelsinger reported in Nature. United States Senate hearings, NIH, and FDA consider the adverse effects of gene therapy.

5. HUGO Ethics Committee Statement on Gene Therapy Research - 1999
Germ-line cell gene therapy avoided, only confronts somatic cell therapy
Main Objectives of Statement:
respond to public concerns about ethical conduct, quality, and safety of somatic gene therapy research
make distinction between somatic therapy from germ-line therapy
encourage adoption of international guidelines
propose framework for public accountability

6. HUGO Ethics Committee Statement on Gene Therapy Research (continued)
Common principles previously established by HUGO in 1996 Statement of the Principled Conduct of Genetics Research:
Recognition that the human genome is part of the common heritage of humanity
Adherence to international norms of human rights
Respect for the values, traditions, culture, and integrity of participants
Acceptance and upholding of human dignity and freedom

7. HUGO Ethics Committee Statement on Gene Therapy Research (continued)
Recommendations by HUGO Committee:
public oversight and ongoing review of research
countries need national ethics bodies that mandate somatic gene therapy
researchers and governments must respond to public concerns about the benefits, risks and ethical conduct of research
all research conducted must abide by stringent quality and safety controls and be in conformity with international norms

8. HUGO Ethics Committee Statement on Gene Therapy Research (continued...)
Recommendations by HUGO Committee (continued):
material conflicts of interest must be identified, declared, and addressed in the most transparent way possible
researchers and media reporting on gene therapy development must do so in an informative and responsible manner
widespread discussion on the appropriateness of possible future gene therapy technology using germ-line cells
It is crucial that the media presents gene therapy responsibly. After all, we are educating an uninformed, moral-driven public.

9. Problems With the HUGO Committee Statement
Why avoid the controversy surrounding germ-line cell therapy?
Lacks descriptive language, very vague.
What kind of material conflicts of interest exist today?
How will the general public be granted oversight over gene therapy development? Federal or state law?

10. Is There Legislation in Place to Protect Your Genetic Information?
There is No Federal policy in place to protect your genetic information unless you work for the Federal government.
There are however, some state policies in place…

11. States Without Legislation Protecting Genetic Information
Alabama
Connecticut
Idaho
Indiana
Iowa
Kansas
Kentucky
Maine
Minnesota
Mississippi
Montana
North Carolina
Ohio
Oklahoma
Pennsylvania
Tennessee
West Virginia
Wisconsin
Wyoming
= 19 States

12. 4 Ethical Yardsticks: Review
Nonmaleficence: Do no harm, avoiding the causation of harm.
Beneficence: Do good.
Respect for autonomy: Respect for the fundamental self-worth, dignity,and decision-making capacity of individuals.
Justice: Distribute benefits, risks and costs fairly.

13. Genetic-ism
Will parents who choose to have babies naturally raise children who will be ostracized in school?
Will a new generation of “perfect” people disrespect and disregard their elders and ancestors?

14. Genetic-ism
Where is the line that separates treatment and enhancement?
What will medical insurance cover?
Could this lead to the creation of a new form of “untouchables?”

15. Justice – Health Insurance
With the completion of the Human Genome Project, the possibility of testing individuals or screening populations for genetic disorders has arisen.
Gene therapy is a reality in today’s society. Hundred’s of clinical trials are performed to treat disorders like cystic fibrosis and Parkinson’s disease.
Should health insurance companies be allowed to discriminate service to individuals based on information from genetic screening?

16. Social Concerns Who will have access to your genetic information?
Who will own your genetic information?

17. Genetic Alliance: Genetic Information Nondiscrimination Act
A bill that will “prohibit discrimination on the basis of genetic information with respect to health insurance and employment.”
prevent health insurers from denying coverage/adjusting premiums based on an individual’s predisposition to a genetic condition
prohibit employer’s from discriminating based on predicitive genetic information
maintain strict use and disclosure requirements of one’s genetic information

18. Playing God…
Do you want to know your child’s negative predispositions even in the case where nothing can be done about them?
Do you want to know your negative genetic predispositions?
What if the tests were wrong?

19. Playing God… Will this lead to more babies being put up for adoption?
Will mothers have abortions when babies are “un-fixable?”

20. Respect for Autonomy
Gene therapy counseling is a much-neglected area of gene therapy.
Gene therapists must be concerned with providing the facts to the patient without soliciting advice.
Genetic counseling is beyond the scope of science. Gene therapy researchers do not have any knowledge in genetic counseling.

21. Gene Therapy Risks
“In nature there are no rewards or punishments; there are consequences.“
Robert Ingersoll
“…for every intended consequence of a complex biologic product, there are unintended consequences.”
Philip Noguchi, M.D.

22. Risks of Gene Therapy
New gene might be inserted into wrong location in the DNA (misfire)
Immune system complications
Vector viruses can infect more than one type of cell
Over-expression of missing protein
DNA could accidentally be introduced into reproductive cells (germ-line gene therapy)

23. Immune System Complications
Immune and Inflammatory responses
Immune system designed to attack foreign invaders
Shutting defense system down risks further advance of illness
Difficulty for gene therapy to be repeated

24. Viral Vectors
Virus could be transmitted from the patient to other individuals
Could disrupt vital genes, causing another disease or a predisposition to cancer

25. Over-Expression Overexpression can contribute to oncogenesis
Overexpression contributes to cancer growth by removing controls on normal cell cycle regulation.

26. Nature vs. Nurture
We still do not know what percentage of our behavior comes from our genetics and what percent comes from our environment.
How will our behavior be affected by “genetic therapy?”

27. Problems with Gene Therapy
Short Lived
Hard to rapidly integrate therapeutic DNA into genome and rapidly dividing nature of cells prevent gene therapy from long time
Would have to have multiple rounds of therapy
Immune Response
new things introduced leads to immune response
increased response when a repeat offender enters
Viral Vectors
patient could have toxic, immune, inflammatory response
also may cause disease once inside
Multigene Disorders
Heart disease, high blood pressure, Alzheimer’s, arthritis and diabetes are hard to treat because you need to introduce more than one gene
May induce a tumor if integrated in a tumor suppressor gene because insertional mutagenesis

28. Unsuccessful Gene therapies
Jesse Gelsinger, a gene therapy patient who lacked ornithine transcarbamylase activity, died in 1999.
Within hours after doctors shot the normal OTC gene attached to a therapeutic virus into his liver, Jesse developed a high fever. His immune system began raging out of control, his blood began clotting, ammonia levels climbed, his liver hemorrhaged and a flood of white blood cells shut down his lungs.
One problem with gene therapy is that one does not have control over where the gene will be inserted into the genome. The location of a gene in the genome is of importance for the degree of expression of the gene and for the regulation of the gene (the so-called "position effect"), and thus the gene regulatory aspects are always uncertain after gene therapy

29. Successful Gene Therapy for Severe Combine Immunodeficiency
Infants with severe combined immunodeficiency are unable to mount an adaptive immune response, because they have a profound deficiency of lymphocytes.
Severe combined immunodeficiency is inherited as an X-linked recessive disease, which for all practical purposes affects only boys. In the other half of the patients with severe combined immunodeficiency, the inheritance is autosomal recessive — and there are several abnormalities in the immune system when the defective gene is encoded on an autosome.

30. What is in the Future For Gene Therapy??
Additional Clinical Trials
More extensive clinical trials for LCA-RPE65
Start new clinical trials for recessively inherited retinal degenerative diseases where there is clear justification to proceed based on animal models

31. More basic research
Build on the successes of gene therapy both in animal models and now human clinical trials
Improve gene delivery through the development of new and improved viral and nonviral vectors

32. Develop methods for treatment of dominant inherited retinal diseases such as autosomal dominant RP and macular degeneration
Typically, these are more complicated in that the defective gene has to be eliminated or inactivated together with the delivery of the normal gene.

33. What Do Scientists Need to Do?
1. Continue to identify genes responsible for various types of retinal degenerative diseases 2. Continue to investigate mechanisms which cause loss in vision and photoreceptor cell death 3. Continue to develop new and improved methods to evaluate treatments (OCT) 4. Continue to develop appropriate animal models to test new vectors and treatments.

34. 5. More pre-clinical and clinical trials as appropriate.
6. Continued international interactions and collaborations to generate new knowledge and methodology.
7. Research Funding - Research is expensive, but in the long term it is well worth the investment in improving the quality of life.
Estimated that NIH has spend over $125,000,000 on LCA – RPE65 studies