Skip to main content
SpringerLink
Log in

Gene Therapy Applications

  • Chapter
  • First Online:
A Handbook of Gene and Cell Therapy

  • 1885 Accesses

Abstract

The development of a therapy for human use entails a complex and long process of studies and validations, first in cells and animal models and later in human subjects. The first step is commonly referred to as preclinical research or development, being important to access the safety and also the efficacy of the therapy proposed. In a gene therapy context, the in vivo preclinical studies, using relevant animal models, are particularly important, as most of the therapies are being studied for the first time. If preclinical studies yield relevant results, therapy can continue its process of development, being then evaluated in clinical trials, which refer to research studies performed in human subjects. In their simplest design, clinical trials aim to evaluate the outcomes of a particular therapy in human subjects under an experimental condition, being also referred to as interventional clinical studies.

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

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 129.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References and Further Reading

  1. Dale O, Salo M (1996) The Helsinki declaration, research guidelines and regulations: present and future editorial aspects. Acta Anaesthesiol Scand 40:771–772

    Article  CAS  PubMed  Google Scholar 

  2. Brandt AM (1978) Racism and research: the case of the Tuskegee Syphilis Study. Hast Cent Rep 8:21–29

    Article  CAS  Google Scholar 

  3. Kane JR, Miska J, Young JS, Kanojia D, Kim JW, Lesniak MS (2015) Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. Neuro Oncol 17(Suppl 2):ii24–ii36

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Gangi A, Zager JS (2017) The safety of talimogene laherparepvec for the treatment of advanced melanoma. Expert Opin Drug Saf 16:265–269

    CAS  PubMed  Google Scholar 

  5. Navarro SA, Carrillo E, Grinan-Lison C, Martin A, Peran M, Marchal JA, Boulaiz H (2016) Cancer suicide gene therapy: a patent review. Expert Opin Ther Pat 26:1095–1104

    Article  CAS  PubMed  Google Scholar 

  6. Fillat C, Carrio M, Cascante A, Sangro B (2003) Suicide gene therapy mediated by the Herpes Simplex virus thymidine kinase gene/Ganciclovir system: fifteen years of application. Curr Gene Ther 3:13–26

    Article  CAS  PubMed  Google Scholar 

  7. Ungerechts G, Bossow S, Leuchs B, Holm PS, Rommelaere J, Coffey M, Coffin R, Bell J, Nettelbeck DM (2016) Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses. Mol Ther Methods Clin Dev 3:16018

    Article  PubMed Central  PubMed  Google Scholar 

  8. Liang M (2018) Oncorine, the world first oncolytic virus medicine and its update in China. Curr Cancer Drug Targets 18:171–176

    Article  CAS  PubMed  Google Scholar 

  9. Matsuda T, Karube H, Aruga A (2018) A comparative safety profile assessment of oncolytic virus therapy based on clinical trials. Ther Innov Regul Sci 52:430–437

    Article  PubMed  Google Scholar 

  10. Karjoo Z, Chen X, Hatefi A (2016) Progress and problems with the use of suicide genes for targeted cancer therapy. Adv Drug Deliv Rev 99:113–128

    Article  CAS  PubMed  Google Scholar 

  11. Amer MH (2014) Gene therapy for cancer: present status and future perspective. Mol Cell Ther 2:27

    Article  PubMed Central  PubMed  Google Scholar 

  12. Marshall HT, Djamgoz MBA (2018) Immuno-oncology: emerging targets and combination therapies. Front Oncol 8:315

    Article  PubMed Central  PubMed  Google Scholar 

  13. Liu Z, Ravindranathan R, Kalinski P, Guo ZS, Bartlett DL (2017) Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun 8:14754

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Zhou R, Caspi RR (2010) Ocular immune privilege. F1000 Biol Rep 2 p.3

    Google Scholar 

  15. Del Amo EM, Rimpela AK, Heikkinen E, Kari OK, Ramsay E, Lajunen T, Schmitt M, Pelkonen L, Bhattacharya M, Richardson D et al (2017) Pharmacokinetic aspects of retinal drug delivery. Prog Retin Eye Res 57:134–185

    Article  PubMed  Google Scholar 

  16. Planul A, Dalkara D (2017) Vectors and gene delivery to the retina. Annu Rev Vis Sci 3:121–140

    Article  PubMed  Google Scholar 

  17. Ku CA, Pennesi ME (2015) Retinal gene therapy: current progress and future prospects. Expert Rev Ophthalmol 10:281–299

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Bennett J (2017) Taking stock of retinal gene therapy: looking back and moving forward. Mol Ther 25:1076–1094

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Nabel EG, Plautz G, Nabel GJ (1990) Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science 249:1285–1288

    Article  CAS  PubMed  Google Scholar 

  20. Yla-Herttuala S, Baker AH (2017) Cardiovascular gene therapy: past, present, and future. Mol Ther 25:1095–1106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Conner JM, Darracq MA, Roberts J, Tuszynski MH (2001) Nontropic actions of neurotrophins: subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation. Proc Natl Acad Sci U S A 98:1941–1946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G et al (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11:551–555

    Article  CAS  PubMed  Google Scholar 

  23. Rafii MS, Baumann TL, Bakay RA, Ostrove JM, Siffert J, Fleisher AS, Herzog CD, Barba D, Pay M, Salmon DP et al (2014) A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer’s disease. Alzheimers Dement 10:571–581

    Article  PubMed  Google Scholar 

  24. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013

    Article  PubMed  Google Scholar 

  25. Axelsen TM, Woldbye DPD (2018) Gene therapy for Parkinson’s disease, an update. J Parkinsons Dis 8:195–215

    Article  PubMed Central  PubMed  Google Scholar 

  26. LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, Kostyk SK, Thomas K, Sarkar A, Siddiqui MS et al (2011) AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol 10:309–319

    Article  CAS  PubMed  Google Scholar 

  27. Palfi S, Gurruchaga JM, Lepetit H, Howard K, Ralph GS, Mason S, Gouello G, Domenech P, Buttery PC, Hantraye P et al (2018) Long-term follow-up of a phase I/II study of ProSavin, a lentiviral vector gene therapy for Parkinson’s disease. Hum Gene Ther Clin Dev 29:148–155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Beck M (2018) Treatment strategies for lysosomal storage disorders. Dev Med Child Neurol 60:13–18

    Article  PubMed  Google Scholar 

  29. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S et al (2013) Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341:1233158

    Article  PubMed  Google Scholar 

  30. Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, Canale S, Lopez ID, Morena F, Calabria A et al (2016) Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 388:476–487

    Article  CAS  PubMed  Google Scholar 

  31. Tardieu M, Zerah M, Husson B, de Bournonville S, Deiva K, Adamsbaum C, Vincent F, Hocquemiller M, Broissand C, Furlan V et al (2014) Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum Gene Ther 25:506–516

    Article  CAS  PubMed  Google Scholar 

  32. Renton AE, Chio A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23

    Article  CAS  PubMed  Google Scholar 

  33. Nóbrega C, Almeida LP (eds) (2018) Polyglutamine diseases. Springer: Gewerbestrasse, Cham, Switzerland

    Google Scholar 

  34. Stechschulte SU1, Joussen AM, von Recum HA, Poulaki V, Moromizato Y, Yuan J, D’Amato RJ, Kuo C, Adamis AP (2001) Rapid ocular angiogenic control via naked DNA delivery to cornea. Invest Ophthalmol Vis Sci 42(9):1975-1979

    Google Scholar 

  35. Touchard E1, Berdugo M, Bigey P, El Sanharawi M, Savoldelli M, Naud MC, Jeanny JC, Behar-Cohen F (2012) Suprachoroidal electrotransfer: a nonviral gene delivery method to transfect the choroid and the retina without detaching the retina. Mol Ther 20(8):1559–1570. doi: https://doi.org/10.1038/mt.2011.304. Epub 2012 Jan 17

  36. Tanelian DL1, Barry MA, Johnston SA, Le T, Smith G ( 1997) Controlled gene gun delivery and expression of DNA within the cornea. Biotechniques 23(3):484–488

    Google Scholar 

  37. Sonoda S, Tachibana K, Yamashita T, Shirasawa M, Terasaki H, Uchino E, Suzuki R, Maruyama K, Sakamoto T (2012) J Ophthalmol. 012; 2012: 412752. Published online 012 Jan 31. doi: https://doi.org/10.1155/2012/412752 PMCID:PMC3307015 PMID: 22518277.

  38. Rajala A1, Wang Y, Zhu Y, Ranjo-Bishop M, Ma JX, Mao C, Rajala RV (2014) Nanoparticle-assisted targeted delivery of eye-specific genes to eyes significantly improves the vision of blind mice in vivo. Nano Lett 14(9):5257–5263. doi: 10.1021/nl502275s. Epub 2014 Aug 12.

    Google Scholar 

  39. Gomes dos Santos AL1, Bochot A, Doyle A, Tsapis N, Siepmann J, Siepmann F, Schmaler J, Besnard M, Behar-Cohen F, Fattal E (2006) Sustained release of nanosized complexes of polyethylenimine and anti-TGF-beta 2 oligonucleotide improves the outcome of glaucoma surgery. J Control Release. 112(3):369–381. Epub 2006 Mar 6

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biomedical Sciences and Medicine & Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, Portugal

    Clévio Nóbrega

  2. Center for Neuroscience and Cell Biology, Universidade de Coimbra, Coimbra, Portugal

    Liliana Mendonça

  3. Centre for Biomedical Research (CBMR), Universidade do Algarve, Faro, Algarve, Portugal

    Carlos A. Matos

Authors
  1. Clévio Nóbrega
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liliana Mendonça
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlos A. Matos
    View author publications

    You can also search for this author in PubMed Google Scholar

Appendices

This Chapter in a Nutshell

  • Preclinical studies normally refer to laboratory studies in cell or animal models that evaluate the safety and efficacy of a therapy.

  • Clinical trials comprise a set of different studies that test the safety, efficacy and side effects of therapy in human subjects.

  • Normally, before receiving marketing authorization, a therapy needs to undergo three different phases of a clinical trial.

  • Gene therapy approaches targeting cancer are grouped into different categories: (1) introduction of suicide genes, which induce the generation of compounds that are toxic to tumor cells; (2) induction of cell lysis using modified viruses; (3) introduction of immunomodulatory genes, aiming to induce or increase the immune system response; and (4) introduction of tumor-suppressor genes, which will block cell division.

  • Suicide gene therapy can be achieved using at least two strategies: an indirect approach, in which therapy is accomplished through an enzyme-activated prodrug that will be converted into a lethal drug in cells, or a direct approach entailing the delivery of proapoptotic genes.

  • Oncolytic gene therapy strategies are based on replicative viruses that specifically target tumor cells.

  • Immunomodulatory gene therapy is based on the recognition that growing tumors actively evade the immune system and that stimulating or enhancing antitumor immunity can be a therapeutic strategy to fight cancer.

  • Tumor-suppressor gene therapy aims to functionally restore mutated/deleted genes and prevent uncontrolled cellular growth.

  • Gene therapy targeting different conditions affecting the eye is among the most advanced strategies developed, mainly due to (1) the easy access to the eye, (2) the easy visualization of the administered therapy, (3) the fact that the eye is an immunologically privileged site, and (4) the fact that the existence of two eyes allows maintaining an untreated contralateral eye as a valuable control.

  • Several gene therapy studies were developed targeting cardiovascular diseases; however, until now no therapy is currently approved.

  • Neurodegenerative diseases are defined by a progressive dysfunction of the nervous system, which is normally translated into severe symptoms and a debilitating phenotype.

  • Due to several important particularities of neurodegenerative diseases, gene therapy arises as a powerful tool to treat them, aiming to restore missing functions, to improve neuronal homeostasis, or ultimately block the molecular pathogenesis.

  • There are multiple examples of gene therapy strategies, developed in both preclinical and clinical studies, that target different neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, among others.

Review Questions

  1. 1.

    What is the main aim of a phase I clinical trial testing of a gene therapy strategy?

    1. (a)

      Access therapy safety

    2. (b)

      Access therapy efficacy

    3. (c)

      Compare the therapy with the gold standard therapy

    4. (d)

      Access the long-term effect of the therapy

    5. (e)

      None of the above

  2. 2.

    Which of the following is not a gene therapy strategy targeting cancer?

    1. (a)

      Suicide gene therapy

    2. (b)

      Oncolytic gene therapy

    3. (c)

      Tumor-suppressor gene therapy

    4. (d)

      Immunomodulatory gene therapy

    5. (e)

      Neurotrophic gene therapy

  3. 3.

    Which feature makes the eye a good target for gene therapy?

    1. (a)

      Difficult access

    2. (b)

      Immunological privilege

    3. (c)

      Is part of the nervous system

    4. (d)

      Non-viral vectors can be used to mediated delivery

    5. (e)

      Has only one type of cells

  4. 4.

    Which of the following viral vectors is more suitable for a direct administration of a gene therapy targeting the brain neurons?

    1. (a)

      Lentiviral vectors

    2. (b)

      Adenoviral vectors

    3. (c)

      Gamma retrovirus-based vectors

    4. (d)

      Adenovirus gutless vectors

    5. (e)

      Baculovirus-based vectors

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Nóbrega, C., Mendonça, L., Matos, C.A. (2020). Gene Therapy Applications. In: A Handbook of Gene and Cell Therapy. Springer, Cham. https://doi.org/10.1007/978-3-030-41333-0_9

Download citation

Publish with us

Policies and ethics

Search

Navigation