Skip to main content
SpringerLink
Log in

Toxicological Aspects in the Regulation of Gene Therapy Medicinal Products

  • Living reference work entry
  • First Online:
Regulatory Toxicology

  • 338 Accesses

Abstract

The safety of Gene Therapy Medicinal Product (GTMPs) is of paramount importance. Therefore, the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and other agencies in the world have issued regulatory guidelines/guidance. Nevertheless, as the field is evolving so fast and safer vectors being developed, a continuous adaptation of the regulation is needed, and not surprisingly, some nonclinical requirements deemed necessary only a few years ago (such as assessing the tumorigenicity of GTMPs in vivo), may appear less relevant today. As any GTMP has its own specificities, a “one-size fits all” toxicology development program cannot be routinely imposed by competent authorities. Rather, a scientifically driven and tailored approach, considering the choice of the delivery vector, the gene to be corrected, and the expected benefit/risk for the targeted indication is recommended for each GTMP. It is advised to present and discuss the development strategy early to regulatory agencies to agree upon the most appropriate design of the nonclinical studies to be conducted.

This chapter informs sponsors on the putative toxicological requirements for their specific GTMP. A review of the evolving regulatory toxicology landscape is provided, for both the EU and USA. To capitalize from the lessons learned from the past to illustrate potential toxicological requirements for new therapies, a benchmark of toxicology studies performed with the eight GTMPs approved by December 31, 2019, in the EU and/or USA is presented.

A hypothesis on the future regulation for the toxicological assessment of GTMPs is provided in the conclusion.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Aiuti A, Roncarolo MG, Naldini L (2017) Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med 9:737–740

    Article  CAS  Google Scholar 

  • Albertson DG, Collins C, McCormick F, Gray JW (2003) Chromosome aberrations in solid tumors. Nat Genet 34:369–376

    Article  CAS  Google Scholar 

  • Alliance for Regenerative Medicine (2018) Annual regenerative medicine data report 2018

    Google Scholar 

  • Alliance for Regenerative Medicine (2019) Quaterly regenerative medicine sector report Q3 2019

    Google Scholar 

  • Baylis F, McLeod M (2017) First-in-human phase 1 CRISPR gene editing cancer trials: are we ready? Curr Gene Ther 17:309–319

    CAS  PubMed  PubMed Central  Google Scholar 

  • Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Göhring G, Steinemann D, Fronza R, Ball CR, Haemmerle R, Naundorf S, Kühlcke K, Rose M, Fraser C, Mathias L, Ferrari R, Abboud MR, Al-Herz W, Kondratenko I, Maródi L, Glimm H, Schlegelberger B, Schambach A, Albert MH, Schmidt M, von Kalle C, Klein C (2014) Gene therapy for Wiskott-Aldrich syndrome – long-term efficacy and genotoxicity. Sci Transl Med 6:227ra33

    Article  Google Scholar 

  • Chandler RJ, Sands MS, Venditti CP (2017) Recombinant adeno-associated viral integration and genotoxicity: insights from animal models. Hum Gene Ther 28:314–322

    Article  CAS  Google Scholar 

  • Colella P, Ronzitti G, Mingozzi F (2018) Emerging issues in AAV-mediated in vivo gene therapy. Mol Ther Methods Clin Dev 8:87–104

    Article  CAS  Google Scholar 

  • Couzin J, Kaiser J (2005) As Gelsinger case ends, gene therapy suffers another blow. Science 307:1028

    Article  CAS  Google Scholar 

  • Elverum K, Whitman M (2019) Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine. Gene Ther. https://doi.org/10.1038/s41434-019-0074-7

  • EMA (2006) Guideline on non-clinical testing for inadvertent germline transmission of gene transfer vectors. EMEA/273974/2005

    Google Scholar 

  • EMA (2008) Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products. EMEA/CHMP/GTWP/125459/2006

    Google Scholar 

  • EMA (2011) Reflection paper on design modifications of gene therapy medicinal products during development. EMA/CAT/GTWP/44236/2009

    Google Scholar 

  • EMA (2012a) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Official Journal, 2001L0083 – EN – 16.11.2012 – 011.001 – 1

    Google Scholar 

  • EMA (2012b) Glybera European Public Assessment Report (EPAR). EMA/882900/2011, EMEA/H/C/002145

    Google Scholar 

  • EMA (2013a) Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products. EMA/CAT/CPWP/686637/2011

    Google Scholar 

  • EMA (2013b) Reflection paper on management of clinical risks deriving from insertional mutagenesis. EMA/CAT/190186/2012

    Google Scholar 

  • EMA (2015) Imlyic European Public Assessment Report (EPAR). EMA/734400/2015/corr. 1, EMEA/H/C/002771/0000

    Google Scholar 

  • EMA (2016) Strimvelis European Public Assessment Report (EPAR). EMA/CHMP/272303/2016 Rev 1, EMEA/H/C/003854/0000

    Google Scholar 

  • EMA (2017) Good Laboratory Practice (GLP) Prrinciples in Relation to ATMPS

    Google Scholar 

  • EMA (2018a) Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products

    Google Scholar 

  • EMA (2018b) Kymriah European Public Assessment Report (EPAR). EMA/485563/2018, EMEA/H/C/004090/0000

    Google Scholar 

  • EMA (2018c) Luxturna European Public Assessment Report (EPAR). EMA/CHMP/700911/2018, EMEA/H/C/004451/0000

    Google Scholar 

  • EMA (2018d) Yescarta European Public Assessment Report (EPAR). EMA/481168/2018, EMEA/H/C/004480/0000

    Google Scholar 

  • EMA (2019a) Draft guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials. EMA/CAT/852602/2018

    Google Scholar 

  • EMA (2019b) Zynteglo autologous CD34+ cells encoding βA-T87Q-globin gene summary of product characteristics.

    Google Scholar 

  • Estêvão D, Costa NR, da Costa RG, Medeiros R (2018) CRISPR-Cas9 therapies in experimental mouse models of cancer. Future Oncol 14:2083–2095

    Article  Google Scholar 

  • FDA (1993) Part II – Department of Health and Human Services Food and Drug Administration – application of current statutory authorities to human somatic cell therapy products and gene therapy products; notice. Fed Regist 58:53248–53251

    Google Scholar 

  • FDA (2006) Guidance for industry – gene therapy clinical trials – observing subjects for delayed adverse events

    Google Scholar 

  • FDA (2013) Guidance for industry – preclinical assessment of investigational cellular and gene therapy products

    Google Scholar 

  • FDA (2020a) Draft guidance for industry – interpreting sameness of gene therapy products under the orphan drug regulations

    Google Scholar 

  • FDA (2020b) Guidance for industry – chemistry, manufacturing, and control (CMC) information for human gene therapy investigational new drug applications (INDs)

    Google Scholar 

  • FDA (2020c) Guidance for industry – human gene therapy for hemophilia

    Google Scholar 

  • FDA (2020d) Guidance for industry – human gene therapy for rare diseases

    Google Scholar 

  • FDA (2020e) Guidance for industry – human gene therapy for retinal disorders

    Google Scholar 

  • FDA (2020f) Guidance for industry – testing of retroviral vector-based human gene therapy products for replication competent retrovirus during product manufacture and patient follow-up

    Google Scholar 

  • FDA. Imlygic (talimogene laherparepvec). Accessed 12 Feb 2020. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/imlygic-talimogene-laherparepvec

  • FDA. Kymriah (tisagenlecleucel). Accessed 12 Feb 2020. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel

  • FDA. Luxturna. Accessed 12 Feb 2020. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna

  • FDA. Yescarta (axicabtagene ciloleucel). Accessed 12 Feb 2020. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel

  • FDA. Zolgensma. Accessed 12 Feb 2020. https://www.fda.gov/vaccines-blood-biologics/zolgensma

  • Goswami R, Subramanian G, Silayeva L, Newkirk I, Doctor D, Chawla K, Chattopadhyay S, Chandra D, Chilukuri N, Betapudi V (2019) Gene therapy leaves a vicious cycle. Front Oncol 9:1–25

    Google Scholar 

  • Gruntman AM, Flotte TR (2018) The rapidly evolving state of gene therapy. FASEB J 32:1733–1740

    Article  CAS  Google Scholar 

  • Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, Clappier E, Caccavelli L, Delabesse E, Beldjord K, Asnafi V, MacIntyre E, Cortivo LD, Radford I, Brousse N, Sigaux F, Moshous D, Hauer J, Borkhardt A, Belohradsky BH, Wintergerst U, Velez MC, Leiva L, Sorensen R, Wulffraat N, Blanche S, Bushman FD, Fischer A, Cavazzana-Calvo M (2008) Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest 118:3132–3142

    Article  CAS  Google Scholar 

  • Hardee CL, Arévalo-Soliz LM, Hornstein BD, Zechiedrich L (2017) Advances in non-viral DNA vectors for gene therapy. Genes 8:65

    Article  Google Scholar 

  • Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157:1262–1278

    Article  CAS  Google Scholar 

  • ICH M3(R2) (2009) Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

    Google Scholar 

  • ICH S2(R1) (2011) Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use

    Google Scholar 

  • ICH S5(R2) (2005) Detection of toxicity to reproduction for medicinal products & toxicity to male fertility

    Google Scholar 

  • ICH S5(R3) (2017) Draft ICH harmonised guideline detection of toxicity to reproduction for human pharmaceuticals S5(R3)

    Google Scholar 

  • ICH S6(R1) (2011) Preclinical safety evaluation of biotechnology-derived pharmaceuticals

    Google Scholar 

  • Modlich U, Bohne J, Schmidt M, von Kalle C, Knöss S, Schambach A, Baum C (2006) Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity. Blood 108:2545–2553

    Article  CAS  Google Scholar 

  • Mokbel K, Mokbel K (2017) CRISPR/Cas9-mediated genome nano-surgery: an update. Biochem Mol Biol J 3:14

    Google Scholar 

  • Morgan RA, Gray D, Lomova A, Kohn DB (2017) Hematopoietic stem cell gene therapy: progress and lessons learned. Cell Stem Cell 21:574–590

    Article  CAS  Google Scholar 

  • Nienhuis AW (2013) Development of gene therapy for blood disorders: an update. Blood 122:1556–1564

    Article  CAS  Google Scholar 

  • Paul-Ehrlich-Institut (PEI) (2020) Gene therapy medicinal products with valid marketing authorization in EU. Accessed 12 Feb 2020. https://www.pei.de/EN/medicinal-products/atmp/gene-therapy-medicinal-products/gene-therapy-node.html

  • Schlimgen R, Howard J, Wooley D, Thompson M, Baden LR, Yang OO, Christiani DC, Mostoslavsky G, Diamond DV, Duane EG, Byers K, Winters T, Gelfand JA, Gary F, Warner Hudson T, Vyas JM (2016) Risks associated with lentiviral vector exposures and prevention strategies. J Occup Environ Med 58:1159–1166

    Article  Google Scholar 

  • Schnepp BC, Reed Clark K, Klemanski DL, Pacak CA, Johnson PR (2003) Genetic fate of recombinant adeno-associated virus vector genomes in muscle. J Virol 77:3495–3504

    Article  CAS  Google Scholar 

  • Schnepp BC, Chulay JD, Ye G-J, Flotte TR, Trapnell BC, Johnson PR (2016) Recombinant adeno-associated virus vector genomes take the form of long-lived, transcriptionally competent episomes in human muscle. Hum Gene Ther 27:32–42

    Article  CAS  Google Scholar 

  • Shim G, Kim D, Park GT, Jin H, Suh S-K, Oh Y-K (2017) Therapeutic gene editing: delivery and regulatory perspectives. Acta Pharmacol Sin 38:738–753

    Article  CAS  Google Scholar 

  • Sibbald, B. 2001. 'Death but one unintended consequence of gene-therapy trial', CMAJ: Canadian Medical Association journal = journal de l'Association medicale canadienne, 164: 1612–12

    Google Scholar 

  • Silva Lima B, Videira MA (2018) Toxicology and biodistribution: the clinical value of animal biodistribution studies. Mol Ther Methods Clin Dev 8:183–197

    Article  CAS  Google Scholar 

  • Srivastava A (2016) In vivo tissue-tropism of adeno-associated viral vectors. Curr Opin Virol 21:75–80

    Article  CAS  Google Scholar 

  • Stirnadel-Farrant H, Kudari M, Garman N, Imrie J, Chopra B, Giannelli S, Gabaldo M, Corti A, Zancan S, Aiuti A, Cicalese MP, Batta R, Appleby J, Davinelli M, Ng P (2018) Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID. Orphanet J Rare Dis 13:49–49

    Article  Google Scholar 

  • White M, Whittaker R, Gándara C, Stoll EA (2017) A guide to approaching regulatory considerations for lentiviral-mediated gene therapies. Human Gene Ther Methods 28:163–176

    Article  CAS  Google Scholar 

  • Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Geigner PL (1990) Direct gene transfer into mouse muscle in vivo. Science 247:1465–1468

    Article  CAS  Google Scholar 

  • World Health Organization (2009) Handbook Good Laboratory Practice (GLP) – quality practices for regulated non-clinical research and development (World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases 2009)

    Google Scholar 

  • Zhang X-H, Tee LY, Wang X-G, Huang Q-S, Yang S-H (2015) Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol Ther Nuc Acids 4:e264–ee64

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are indebted to Mr. Francois Gianelli and Dr Gopalan Narayanan for their kind review of the manuscript.

Disclaimer

Any views and opinions expressed in this article are those of the authors and do not necessarily reflect those of any institutions the authors are associated with

Author information

Authors and Affiliations

  1. Voisin Consulting Life Sciences, Boulogne, Paris, France

    Cécile F. Rousseau, Emmanuelle Sabbah-Petrover, Deborah Revaud & Emmanuelle M. Voisin

  2. Nutrition + HealthCARE, Vevey, Switzerland

    Manfred Ruthsatz

  3. Voisin Consulting Life Sciences, Lausanne, Switzerland

    Carlo Chiavaroli

Authors
  1. Cécile F. Rousseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emmanuelle Sabbah-Petrover
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deborah Revaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emmanuelle M. Voisin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manfred Ruthsatz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlo Chiavaroli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlo Chiavaroli .

Editor information

Editors and Affiliations

  1. Universität München Inst. Pharmakologie und Toxikologie, München, Germany

    Franz-Xaver Reichl

  2. Tübingen, Germany

    Michael Schwenk

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer-Verlag GmbH Germany, part of Springer Nature

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Rousseau, C.F., Sabbah-Petrover, E., Revaud, D., Voisin, E.M., Ruthsatz, M., Chiavaroli, C. (2020). Toxicological Aspects in the Regulation of Gene Therapy Medicinal Products. In: Reichl, FX., Schwenk, M. (eds) Regulatory Toxicology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-36206-4_141-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-36206-4_141-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-36206-4

  • Online ISBN: 978-3-642-36206-4

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation