In her 60-minute presentation, Professor Charo addressed Ethical Challenges in Trials of Human Genome Editing and Gene Therapy, as gene therapy and genome editing clinical trials involve ethical challenges not always found in other areas of research.

1. Ethical Challenges in
Human Genome
Editing and Gene
Therapy Trials
R. Alta Charo, J.D.
Knowles Professor Emerita
of Law & Bioethics
University of Wisconsin
• 29 Sept 2021

2. Conflict and
Bias
• Co-Chair, NASEM genome editing consensus study (2017)
• Member, WHO genome editing expert advisory committee
• Member, Organizing Committees, Second (2018) and Third
(2022) International Summits on Genome Editing
• Member, Steering Committee on Clinical Guidelines,
International Society for Stem Cell Research
• Consulting with:
• Janssen/Johnson&Johnson
• Vertex Pharmaceuticals
• eGenesis
• Colossal
• BioMADE

3. 2017

6. Where We Are
• To date, almost 2600 gene therapy clinical trials
have been completed, are ongoing or have been
approved worldwide.
• Recently, in vivo genome editing trials have also
been authorized.
• FDA expects the number of therapies meeting
approval will increase rapidly, up to around 10 to
20 per year by 2025

7. Ethical challenges -- early-phase clinical CGT trials
• Assessing risk-to-benefit ratio
• Inclusion/exclusion criteria
• Informed consent; risk of therapeutic misconception
• Potential for prolonged biological activity after a single administration
• High potential for immunogenicity
• Relatively invasive procedures to administer the product
• Dynamic nature of cells (stem cells may transform, form tumors)
• Expression may be uncontrolled, interfere with function of a system
• Might cause neighboring genes to generate benign or malignant tumors
• Riva, L., Petrini, C. A few ethical issues in translational research for gene and cell therapy. J Transl Med 17, 395 (2019).

8. Early Setbacks
• Jesse Gelsinger: died of complications
from an inflammatory response shortly
after receiving a dose of experimental
adenovirus vector.
• His death halted all gene therapy trials in
the United States for a time
• Gene therapy trials aimed at treating
children with X-linked Severe Combined
Immune Deficiency (SCID)
• Despite successes, some children
developed leukemia.

9. Recent
High-Profile
Setbacks
Gene therapy for hemophilia A is rejected by FDA
A third clinical trial participant dies after receiving
experimental gene therapy for a rare
neuromuscular disease.
In another hemophilia study, a volunteer is
diagnosed with liver cancer
A key study on gene therapy for Duchenne’s MD
missed one of its main goals.

11. Vector Concerns
• >40 therapies with these vectors submitted to FDA in 2020 for consult ahead of
human testing; >10 in consideration for human testing.
• FDA safety concerns: liver toxicity to kidney injury to loss of neurons.
• Merits and limitations of animal studies:
• Which animals should be used to best model what might happen in humans?
• How can patients be screened for risk of experiencing adverse liver events?
• What should be used with gene therapy treatment itself to mitigate the risks?
• Should there be a limit on vector dosing?

12. Long-term
Surveillance
Genetically modified cells are complex – must observe
how cells behave over time.
Even more complicated with genetically modified hematopoietic
stem cells (HSCs) - these “forever cells” stay with the patient.
Treat a two-month-old infant: but stability, adverse
effect monitoring and therapeutic endpoint make
take 70 years
Consider effects of personnel changes; different
doctors and teams
Consider patient’s lived experience (Is the genetic
modification the reason I am experiencing XX now?)

13. ISSCR Guidelines: Issues Particular to Genome
Editing of Somatic Stem Cells
• Clinical use of genetically altered somatic stem cells should be reserved for
the treatment or correction of severe disease and disability.
• genetic alteration for non-serious conditions or for enhancement of body
performance or features … should be discouraged: the potential benefits
are marginal and cannot offset the risks at this time; they are unlikely to
have public support; and they could bring the field into disrepute. The
current risks associated with the methods also make it inadvisable to use
them in attempts to confer disease resistance.

14. In utero gene therapy
• In utero stem cell-based or gene-based
intervention (whether based on gene
replacement or genome editing) advantages:
• intervention before tissue damage is
established; tissue/cells have best growth
and regeneration potential;
• Better bio-distribution while tissue barriers
are still immature and target cell
population is smaller size
• low risk of eliciting immune response
because of the incomplete development of
the adaptive immune system

15. Concerns
with In
Utero
Intervention
May increase the risk of genotoxicity - high
rate of cell proliferation and increased
proportion of self- renewing progenitors.
Broad biodistribution may also reach
unintended tissues or cell populations that
are otherwise shielded at older ages, such as
germline cells.
Any acute or delayed toxicity may have far
more damaging consequences than observed
when genome editing is performed at later
stages of life, including teratogenicity.

16. Ethical and
Legal
Complexities
to Discuss
During
Consent
Process
Possibility that even if this prenatal intervention is
successful, there might nonetheless be a
miscarriage, a stillbirth, or a child born with serious
health problems.
Availability (medically, legally and logistically) of
abortion in case intervention fails
Legal requirement, if any, of consent by paternal
progenitor and/or intended rearing partner.

17. Access and
Equity

18. “Gene therapy companies have an ethical
obligation to develop expanded access
policies”
Lisa Kearns et al
Molecular Therapy
Volume 29, Issue 4, P1367-1369
(7 April 2021)

19. 2019

20. Sickle Cell
Disease

21. Sickle Cell
Disease
“After undergoing myeloablation, two patients — one with TDT and the other
with SCD — received autologous CD34+ cells edited with CRISPR-Cas9 targeting
the same BCL11A enhancer. More than a year later, both patients had high levels
of allelic editing in bone marrow and blood, increases in fetal hemoglobin that
were distributed pancellularly, transfusion independence, and (in the patient with
SCD) elimination of vaso-occlusive episodes.”
2021

22. Many Diseases Are Promising
Targets for Gene Therapy
Figure reproduced from The Journal of Gene Medicine, © 2017 John Wiley and Sons Ltd3.
1. Beitelshees M, et al. Discov Med 2017;24(134):313–322; 2. Ginn SL, et al. J Gene Med 2018;20(5):e3015; 3. The Journal of Gene Medicine. Indications addressed by gene therapy clinical trials. December 2019. Available at: http://www.abedia.com/wiley/indications.php. Accessed 30 June 2020.
22
Much of the previous research into gene
therapy has focused on cancer and
monogenic diseases1
• Improved understanding of the genetics of
inherited diseases is increasingly
prompting research into gene therapy
applications in a broader range of
disorders1
• Clinical trials of gene therapy for
infectious diseases, cardiovascular disease,
neurological diseases, and inflammatory
diseases are ongoing2,3
Indications Addressed by Gene Therapy Clinical Trials3
66.6%
11.9%
6.1%
6.1%
1.8%
1.2%
0.5% 2.1% 1.7%
2.0%
Cancer (n=2016)
Monogenic diseases (n=359)
Infectious diseases (n=184)
Cardiovascular diseases (n=184)
Neurological diseases (n=54)
Ocular diseases (n=37)
Inflammatory diseases (n=15)
Other diseases (n=64)
Gene marking (n=50)
Healthy volunteers (n=62)

23. Payment
Models
Current system – major investment, uncertain
approval, high cost during initial period of exclusivity
• Note too the special platform and manufacturing costs for CGTs
Small populations – little opportunity for profit due
to scale
Private insurance – Payor for high upfront cost may
not be same company to reap the long-term savings
Alternate Models?
• Milestone payments
• Value systems
• Special common funds

24. Epigenetic
Editing
• Epigenetic
modifications, such
as DNA methylation
and histone
modification, alter
DNA accessibility
and chromatin
structure, thereby
regulating patterns
of gene expression.
https://gersbach.bme.duke.edu/research/epigenome-editing-and-gene-regulation

25. Epigenetic
Editing and
Dual-Use?

26. Closing
Comments
RAPIDLY EXPANDING
RANGE OF
POSSIBILITIES
INCREASED
COMMERCIAL
INTEREST
UNCERTAIN PAYMENT
CAPACITY
EQUITABLE ACCESS
CHALLENGES