1932

Abstract

Manipulation of a patient's genome for therapeutic ends is being attempted through numerous methods, some of which have resulted in disease-modifying interventions. The much anticipated promise of somatic gene therapy is starting to pay off; however, there remain many scientific unknowns, including concerns about safety and durability. A significant ethical concern is that of access to these novel interventions, an issue that is normally framed in terms of the high costs of approved products. I describe how access issues permeate gene therapy long before there is any commercial product and how even upstream decisions—such as choices of indication to pursue, viral vector, and where to site a trial—have significant implications for access to resultant products in both the developmental and commercial stages.

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2024-08-27
2025-06-17
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Literature Cited

  1. 1.
    Adair JE, Androski L, Bayigga L, Bazira D, Brandon E, et al. 2023.. Towards access for all: 1st working group report for the Global Gene Therapy Initiative (GGTI). . Gene Ther. 30:(3–4):21621
    [Crossref] [Google Scholar]
  2. 2.
    Anderson A, Borfitz D, Getz K. 2018.. Global public attitudes about clinical research and patient experiences with clinical trials. . JAMA Netw Open. 1:(6):e182969
    [Crossref] [Google Scholar]
  3. 3.
    Benjaminy S, Macdonald I, Bubela T. 2014.. “Is a cure in my sight?” Multi-stakeholder perspectives on phase I choroideremia gene transfer clinical trials. . Genet. Med. 16:(5):37985
    [Crossref] [Google Scholar]
  4. 4.
    Bétourné A, Walls RL, Bateman-House A, Ollivier C, Huynh H, et al. 2022.. Rare Diseases Cures Accelerator Data and Analytics Platform (RDCA-DAP) best practices and recommendations for FAIR data, toward alignment with international regulatory agencies. Rep., Crit. Path Inst., Tucson, AZ:
    [Google Scholar]
  5. 5.
    Biesecker BB, Peters KF, Resta R. 2019.. Advanced Genetic Counseling Theory and Practice. New York:: Oxford Univ. Press
    [Google Scholar]
  6. 6.
    Blendon RJ, Gorski MT, Benson JM. 2016.. The public and the gene-editing revolution. . N. Engl. J. Med. 374:(15):140611
    [Crossref] [Google Scholar]
  7. 7.
    Brooks SP, Benjaminy S, Bubela T. 2019.. Participant perspectives on a phase I/II ocular gene therapy trial. . Ophthalmic Genet. 40:(3):27681
    [Crossref] [Google Scholar]
  8. 8.
    Buedo P, Bianchini A, Klas K, Waligora M. 2023.. Bioethics of somatic gene therapy: What do we know so far?. Curr. Med. Res. Opin. 39:(10):135565
    [Crossref] [Google Scholar]
  9. 9.
    Calcedo R, Vandenberghe LH, Gao G, Lin J, Wilson JM. 2009.. Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. . J. Infect. Dis. 199:(3):38190
    [Crossref] [Google Scholar]
  10. 10.
    Carbone F, Montecucco F. 2024.. Facing ethical concerns in the age of precise gene therapy: outlook on inherited arrhythmias. . World J. Cardiol. 16:(2):6466
    [Crossref] [Google Scholar]
  11. 11.
    Cent. Biol. Eval. Res. 2022.. Long term follow-up after administration of human gene therapy products: guidance for industry. Guid. Doc., Cent. Biol. Eval. Res., US Food Drug Adm., US Dep. Health Hum. Serv., Silver Spring, MD:. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-follow-after-administration-human-gene-therapy-products
    [Google Scholar]
  12. 12.
    Cornu TI, Mussolino C, Müller MC, Wehr C, Kern WV, et al. 2021.. HIV gene therapy: an update. . Hum. Gene Ther. 32:(1–2):5265
    [Crossref] [Google Scholar]
  13. 13.
    DeGregory L. 2018.. The rescue: banking on a cure. . Tampa Bay Tribune, Dec. 17. https://projects.tampabay.com/projects/2018/narratives/lincolns-shot/the-rescue
    [Google Scholar]
  14. 14.
    Doudna JA. 2020.. The promise and challenge of therapeutic genome editing. . Nature 578:(7794):22936
    [Crossref] [Google Scholar]
  15. 15.
    Fletcher S, Jenner K, Holland M, Khair K. 2024.. Barriers to gene therapy, understanding the concerns people with haemophilia have: an exigency sub-study. . Orphanet J. Rare Dis. 19:(1):59
    [Crossref] [Google Scholar]
  16. 16.
    High KA. 2020.. Turning genes into medicines—what have we learned from gene therapy drug development in the past decade?. Nat. Commun. 11::5821
    [Crossref] [Google Scholar]
  17. 17.
    Horng S, Grady C. 2003.. Misunderstanding in clinical research: distinguishing therapeutic misconception, therapeutic misestimation, and therapeutic optimism. . IRB 25:(1):1116
    [Crossref] [Google Scholar]
  18. 18.
    Horton RH, Saade D, Markati T, Harriss E, Bönnemann CG, et al. 2022.. A systematic review of adeno-associated virus gene therapies in neurology: the need for consistent safety monitoring of a promising treatment. . J. Neurol. Neurosurg. Psychiatry 93:(12):127688
    [Google Scholar]
  19. 19.
    Hussain SB, Quittner AL, Brown M, Li-Rosi AM. 2020.. Understanding access to genomics in an ethnically diverse south Florida population: a comparison of demographics in odyssey and rapid whole genome sequencing programs. . J. Genet. Couns. 29:(4):55361
    [Crossref] [Google Scholar]
  20. 20.
    Iyer AA, Saade D, Bharucha-Goebel D, Foley AR, Averion G, et al. 2021.. Ethical challenges for a new generation of early-phase pediatric gene therapy trials. . Genet. Med. 23::205766
    [Crossref] [Google Scholar]
  21. 21.
    Kimberly L, Hunt C, Beaverson K, James E, Bateman-House A, et al. 2023.. The lived experience of pediatric gene therapy: a scoping review. . Hum. Gene Ther. 34:(23–24):118089
    [Crossref] [Google Scholar]
  22. 22.
    Kimmelman J. 2020.. Why IRBs should protect bystanders in human research. . Bioethics 34:(9):93336
    [Crossref] [Google Scholar]
  23. 23.
    King NMP, Henderson GE, Churchill LR, Davis AM, Hull SC, et al. 2005.. Consent forms and the therapeutic misconception: the example of gene transfer research. . IRB 27:(1):18
    [Crossref] [Google Scholar]
  24. 24.
    Klamroth R, Hayes G, Andreeva T, Gregg K, Suzuki T, et al. 2022.. Global seroprevalence of pre-existing immunity against AAV5 and other AAV serotypes in people with hemophilia A. . Hum. Gene Ther. 33:(7–8):43241
    [Crossref] [Google Scholar]
  25. 25.
    Kuzmin DA, Shutova MV, Johnston NR, Smith OP, Fedorin VV, et al. 2021.. The clinical landscape for AAV gene therapies. . Nat. Rev. Drug Discov. 20::17374
    [Crossref] [Google Scholar]
  26. 26.
    Leibowitz ML, Papathanasiou S, Doerfler PA, Blaine LJ, Sun L, et al. 2021.. Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing. . Nat. Genet. 53:(6):895905
    [Crossref] [Google Scholar]
  27. 27.
    Lek A, Wong B, Keeler A, Blackwood M, Ma K, et al. 2023.. Death after high-dose rAAV9 gene therapy in a patient with Duchenne's muscular dystrophy. . N. Engl. J. Med. 389:(13):120310
    [Crossref] [Google Scholar]
  28. 28.
    Lekstrom-Himes J, Augustine EF, Brower A, Defay T, Finkel R, et al. 2023.. Data sharing to advance gene-targeted therapies in rare diseases. . Am. J. Med. Genet. C 193:(1):8798
    [Crossref] [Google Scholar]
  29. 29.
    Li X, Wei X, Lin J, Ou L. 2022.. A versatile toolkit for overcoming AAV immunity. . Front. Immunol. 13::991832
    [Crossref] [Google Scholar]
  30. 30.
    Liao WW, Asri M, Ebler J, Doerr D, Haukness M, et al. 2023.. A draft human pangenome reference. . Nature 617:(7960):31224
    [Crossref] [Google Scholar]
  31. 31.
    Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, et al. 2018.. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. . Genet. Med. 20:(4):43543
    [Crossref] [Google Scholar]
  32. 32.
    Lovelace B Jr., Kopf M. 2023.. FDA approves cure for sickle cell disease, the first treatment to use gene-editing tool CRISPR. . NBC News, Dec. 8.. https://www.nbcnews.com/health/health-news/fda-approves-cure-sickle-cell-disease-first-treatment-use-gene-editing-rcna127979
    [Google Scholar]
  33. 33.
    Natl. Acad. Sci. Eng. Med. 2023.. Third International Summit on Human Genome Editing: Expanding Capabilities, Participation, and Access; Proceedings of a Workshop—in Brief. Washington, DC:: Natl. Acad. Press. https://www.ncbi.nlm.nih.gov/books/NBK593530
    [Google Scholar]
  34. 34.
    Natl. Comm. Prot. Hum. Subj. Biomed. Behav. Res. 1978.. The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. Rep., Natl. Comm. Prot. Hum. Subj. Biomed. Behav. Res., Dep. Health Educ. Welf., Washington, DC:. https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report
    [Google Scholar]
  35. 35.
    Nelles M, Stieger K, Preising MN, Kruse J, Lorenz B. 2015.. Shared decision-making, control preferences and psychological well-being in patients with RPE65 deficiency awaiting experimental gene therapy. . Ophthalmic Res. 54:(2):96102
    [Crossref] [Google Scholar]
  36. 36.
    Paquin RS, Fischer R, Mansfield C, Mange B, Beaverson K, et al. 2019.. Priorities when deciding on participation in early-phase gene therapy trials for Duchenne muscular dystrophy: a best-worst scaling experiment in caregivers and adult patients. . Orphanet J. Rare Dis. 14::102
    [Crossref] [Google Scholar]
  37. 37.
    Pediatr. Gene Ther. Med. Ethics Work. Group. 2020.. Listening session with clinicians and caregivers, Pediatr. . Gene Ther. Med. Ethics Work. Group, Div. Med. Ethics, NYU Grossman Sch. Med., New York:, Feb. 26
  38. 38.
    Pediatr. Gene Ther. Med. Ethics Work. Group. 2023.. Antibodies to viral vectors in GT research: best practices for sponsor policies & communication. . YouTube. https://www.youtube.com/watch?v=cLo5YT5HdvU
    [Google Scholar]
  39. 39.
    Phillips KA, Douglas MP, Wordsworth S, Buchanan J, Marshall DA. 2021.. Availability and funding of clinical genomic sequencing globally. . BMJ Glob. Health 6:(2):e004415
    [Crossref] [Google Scholar]
  40. 40.
    PTC Ther. 2015.. PTC announces Translarna™ access program in Duchenne muscular dystrophy for siblings of patients participating in PTC clinical trials. . PR Newswire, Mar. 3. https://www.prnewswire.com/news-releases/ptc-announces-translarna-access-program-in-duchenne-muscular-dystrophy-for-siblings-of-patients-participating-in-ptc-clinical-trials-300044303.html
    [Google Scholar]
  41. 41.
    Ringo A. 2018.. Understanding deafness: Not everyone wants to be “fixed.”. Atlantic, Aug. 9. https://www.theatlantic.com/health/archive/2013/08/understanding-deafness-not-everyone-wants-to-be-fixed/278527
    [Google Scholar]
  42. 42.
    Saha K, Sontheimer EJ, Brooks PJ, Dwinell MR, Gersbach CA, et al. 2021.. The NIH somatic cell genome editing program. . Nature 592:(7853):195204
    [Crossref] [Google Scholar]
  43. 43.
    Spartalis M, Spartalis E, Siasos G. 2023.. Inherited arrhythmias and gene therapy: Are there any ethical considerations to take into account?. World J. Cardiol. 15:(12):62326
    [Crossref] [Google Scholar]
  44. 44.
    Srivastava A. 2023.. Rationale and strategies for the development of safe and effective optimized AAV vectors for human gene therapy. . Mol. Ther. Nucleic Acids 32::94959
    [Crossref] [Google Scholar]
  45. 45.
    US Food Drug Adm. 2020.. FDA continues strong support of innovation in development of gene therapy products. News Release, Jan. 20 , US Food Drug Adm., Silver Spring, MD:. https://www.fda.gov/news-events/press-announcements/fda-continues-strong-support-innovation-development-gene-therapy-products
    [Google Scholar]
  46. 46.
    US Food Drug Adm. 2022.. FDA approves first gene therapy to treat adults with hemophilia B. News Release, Nov. 22 , US Food Drug Adm., Silver Spring, MD:. https://web.archive.org/web/20240117103619/https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b
    [Google Scholar]
  47. 47.
    US Food Drug Adm. 2024.. Approved cellular and gene therapy products. . US Food and Drug Administration. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products
    [Google Scholar]
  48. 48.
    US Food Drug Adm. 2024.. Elevidys. . US Food and Drug Administration. https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/elevidys
    [Google Scholar]
  49. 49.
    US Food Drug Adm. 2024.. FDA approves first gene therapy for children with metachromatic leukodystrophy. News Release, Mar. 18 , US Food Drug Adm., Silver Spring, MD:. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystrophy
    [Google Scholar]
  50. 50.
    Watson MS, Lloyd-Puryear MA, Howell RR. 2022.. The progress and future of US newborn screening. . Int. J. Neonatal Screen. 8:(3):41
    [Crossref] [Google Scholar]
  51. 51.
    Webb J, Shah LD, Bateman-House A. 2021.. Siblings and discordant eligibility for gene therapy research: considering parental requests for non-trial “compassionate use. .” Clin. Ethics 16:(4):35963
    [Crossref] [Google Scholar]
  52. 52.
    Yu TW, Kingsmore SF, Green RC, MacKenzie T, Wasserstein M, et al. 2023.. Are we prepared to deliver gene-targeted therapies for rare diseases?. Am. J. Med. Genet. C 193:(1):712
    [Crossref] [Google Scholar]
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