THE DEVELOPMENT of a SAFE and OPTIMIZED GENE THERAPY for HUMAN DISEASES

Alva Supit, Linda Tompodung

Abstract


Gene therapy is the therapeutic delivery of a gene or nucleic acid into a patient’s cells to cure or alleviate the symptoms of a disease that was caused by genetic malfunction, either gain- of loss-of function. Throughout the years, gene therapy has been faced with fluctuations of development before reaching its current stage. In the early stage, gene therapy was concerned to possess several problems such as toxicity, mutagenesis, and adverse immune responses which would harm the patients, instead of benefiting them. Fortunately, gene therapy has currently reached the phase where its administration can be performed in a safe, controllable manner with a good tolerability and excellent therapeutic effect. This review will recite the development of gene therapy research, highlight the vector-related safety issues, and discuss the latest updates in recent clinical trials with promising results in correcting gene defects in the cell, reducing the symptoms of the disease, as well as improving the patient’s quality of life.


Keywords


gene therapy, clinical trial, genetic disease, safety

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References


Aiuti, A., Cattaneo, F., Galimberti, S., Benninghoff, U., Cassani, B., Callegaro, L., … Roncarolo, M.-G. (2009). Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency. New England Journal of Medicine, 360(5), 447–458. http://doi.org/10.1056/NEJMoa0805817

Alton, E. W., Armstrong, D. K., Ashby, D., Bayfield, K. J., Bilton, D., Bloomfield, E. V, … Consortium, on behalf of the U. C. F. G. T. (2016). A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy in patients with cystic fibrosis. NIHR Journals Library. http://doi.org/10.3310/EME03050

Alton, E. W. F. W., Armstrong, D. K., Ashby, D., Bayfield, K. J., Bilton, D., Bloomfield, E. V, … UK Cystic Fibrosis Gene Therapy Consortium. (2015). Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. The Lancet Respiratory Medicine, 3(9), 684–691. http://doi.org/10.1016/S2213-2600(15)00245-3

Anderson, W. F. (1984). Prospects for human gene therapy. Science (New York, N.Y.), 226(4673), 401–9. http://doi.org/10.1126/SCIENCE.6093246

Bharucha-Goebel, D., & Kaufmann, P. (2017). Treatment Advances in Spinal Muscular Atrophy. Current Neurology and Neuroscience Reports, 17(11), 91. http://doi.org/10.1007/s11910-017-0798-y

Bordignon, C., Notarangelo, L. D., Nobili, N., Ferrari, G., Casorati, G., Panina, P., … Fischer, A. (1995). Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science (New York, N.Y.), 270(5235), 470–5. http://doi.org/10.1126/science.288.5466.669

Buckley, R. H. (2004). M olecular D efects in H uman S evere C ombined I mmunodeficiency and A pproaches to I mmune R econstitution. Annual Review of Immunology, 22(1), 625–655. http://doi.org/10.1146/annurev.immunol.22.012703.104614

Edelstein, M. L., Abedi, M. R., & Wixon, J. (2007). Gene therapy clinical trials worldwide to 2007—an update. The Journal of Gene Medicine, 9(10), 833–842. http://doi.org/10.1002/jgm.1100

Eichler, F., Duncan, C., Musolino, P. L., Orchard, P. J., De Oliveira, S., Thrasher, A. J., … Williams, D. A. (2017). Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. New England Journal of Medicine, 377(17), 1630–1638. http://doi.org/10.1056/NEJMoa1700554

Fletcher, J. C. (1983). Moral Problems and Ethical Issues in Prospective Human Gene Therapy. Virginia Law Review, 69(3), 515. http://doi.org/10.2307/1072768

Gabriel, R., von Kalle, C., & Schmidt, M. (2015). Mapping the precision of genome editing. Nature Biotechnology, 33(2), 150–152. http://doi.org/10.1038/nbt.3142

Gaudet, D., Méthot, J., Déry, S., Brisson, D., Essiembre, C., Tremblay, G., … van Deventer, S. (2013). Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Therapy, 20(4), 361–369. http://doi.org/10.1038/gt.2012.43

George, L. A., Sullivan, S. K., Giermasz, A., Rasko, J. E. J., Samelson-Jones, B. J., Ducore, J., … High, K. A. (2017). Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. New England Journal of Medicine, 377(23), 2215–2227. http://doi.org/10.1056/NEJMoa1708538

Ginn, S. L., Alexander, I. E., Edelstein, M. L., Abedi, M. R., & Wixon, J. (2013). Gene therapy clinical trials worldwide to 2012 - an update. The Journal of Gene Medicine, 15(2), 65–77. http://doi.org/10.1002/jgm.2698

Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M., & Abedi, M. R. (2018). Gene therapy clinical trials worldwide to 2017: An update. The Journal of Gene Medicine, 20(5), e3015. http://doi.org/10.1002/jgm.3015

Hacein-Bey-Abina, S., Le Deist, F., Carlier, F., Bouneaud, C., Hue, C., De Villartay, J.-P., … Cavazzana-Calvo, M. (2002). Sustained Correction of X-Linked Severe Combined Immunodeficiency by ex Vivo Gene Therapy. New England Journal of Medicine, 346(16), 1185–1193. http://doi.org/10.1056/NEJMoa012616

Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., McIntyre, E., … Fischer, A. (2003). A Serious Adverse Event after Successful Gene Therapy for X-Linked Severe Combined Immunodeficiency. New England Journal of Medicine, 348(3), 255–256. http://doi.org/10.1056/NEJM200301163480314

Hackam, D. G., & Redelmeier, D. A. (2006). Translation of Research Evidence From Animals to Humans. JAMA, 296(14), 1727. http://doi.org/10.1001/jama.296.14.1731

Henrard, S., Devleesschauwer, B., Beutels, P., Callens, M., De Smet, F., Hermans, C., & Speybroeck, N. (2014). The health and economic burden of haemophilia in Belgium: a rare, expensive and challenging disease. Orphanet Journal of Rare Diseases, 9, 39. http://doi.org/10.1186/1750-1172-9-39

Jacobson, S. G., Cideciyan, A. V., Ratnakaram, R., Heon, E., Schwartz, S. B., Roman, A. J., … Hauswirth, W. W. (2012). Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations. Archives of Ophthalmology, 130(1), 9. http://doi.org/10.1001/archophthalmol.2011.298

Kumar, S. R., Markusic, D. M., Biswas, M., High, K. A., & Herzog, R. W. (2016). Clinical development of gene therapy: results and lessons from recent successes. Molecular Therapy - Methods & Clinical Development, 3, 16034. http://doi.org/10.1038/mtm.2016.34

Lam, B. L., Davis, J. L., Gregori, N. Z., MacLaren, R. E., Girach, A., Verriotto, J. D., … Feuer, W. J. (2019). Choroideremia Gene Therapy Phase 2 Clinical Trial: 24-Month Results. American Journal of Ophthalmology, 197, 65–73. http://doi.org/10.1016/J.AJO.2018.09.012

Mannucci, P. M. (2003). Hemophilia: treatment options in the twenty-first century. Journal of Thrombosis and Haemostasis, 1(7), 1349–1355. http://doi.org/10.1046/j.1538-7836.2003.00262.x

Mannucci, P. M., Mancuso, M. E., & Santagostino, E. (2012). How I treat How we choose factor VIII to treat hemophilia. Blood, 119(18). http://doi.org/10.1182/blood

Mendell, J. R., Al-Zaidy, S., Shell, R., Arnold, W. D., Rodino-Klapac, L. R., Prior, T. W., … Kaspar, B. K. (2017). Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine, 377(18), 1713–1722. http://doi.org/10.1056/NEJMoa1706198

Morsy, M. A., Zhao, J. Z., Ngo, T. T., Warman, A. W., O’Brien, W. E., Graham, F. L., & Caskey, C. T. (1996). Patient selection may affect gene therapy success. Dominant negative effects observed for ornithine transcarbamylase in mouse and human hepatocytes. The Journal of Clinical Investigation, 97(3), 826–32. http://doi.org/10.1172/JCI118482

Naldini, L. (2015). Gene therapy returns to centre stage. Nature, 526(7573), 351–360. http://doi.org/10.1038/nature15818

Nault, J.-C., Datta, S., Imbeaud, S., Franconi, A., Mallet, M., Couchy, G., … Zucman-Rossi, J. (2015). Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nature Genetics, 47(10), 1187–1193. http://doi.org/10.1038/ng.3389

Powell, J. S. ., & et al. (2001). Results from one year follow up of a phase I trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood, 98(11), 693a.

Rangarajan, S., Walsh, L., Lester, W., Perry, D., Madan, B., Laffan, M., … Pasi, K. J. (2017). AAV5–Factor VIII Gene Transfer in Severe Hemophilia A. New England Journal of Medicine, NEJMoa1708483. http://doi.org/10.1056/NEJMoa1708483

Raper, S. E., Chirmule, N., Lee, F. S., Wivel, N. A., Bagg, A., Gao, G., … Batshaw, M. L. (2003). Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Molecular Genetics and Metabolism, 80(1–2), 148–158. http://doi.org/10.1016/J.YMGME.2003.08.016

Rosenberg, S. A., Aebersold, P., Cornetta, K., Kasid, A., Morgan, R. A., Moen, R., … Anderson, W. F. (1990). Gene Transfer into Humans — Immunotherapy of Patients with Advanced Melanoma, Using Tumor-Infiltrating Lymphocytes Modified by Retroviral Gene Transduction. New England Journal of Medicine, 323(9), 570–578. http://doi.org/10.1056/NEJM199008303230904

Siddiqi, A.-A., Ebrahim, S. H., Soucie, J. M., Parker, C. S., & Atrash, H. K. (2010). Burden of Disease Resulting from Hemophilia in the U.S. American Journal of Preventive Medicine, 38(4), S482–S488. http://doi.org/10.1016/j.amepre.2009.12.016

Somia, N., & Verma, I. M. (2000). Gene therapy: trials and tribulations. Nature Reviews Genetics, 1(2), 91–99. http://doi.org/10.1038/35038533

Supit, A. S. A. (2017). Improving the function of CRISPR-Cas9 for genome editing therapy: Editing the editor. Jurnal Bioteknologi & Biosains Indonesia (JBBI), 4(1), 44. http://doi.org/10.29122/jbbi.v4i1.2068

Thomas, C. E., Ehrhardt, A., & Kay, M. A. (2003). Progress and problems with the use of viral vectors for gene therapy. Nature Reviews Genetics, 4(5), 346–358. http://doi.org/10.1038/nrg1066

van den Berg, H. M. (2017). A Cure for Hemophilia within Reach. New England Journal of Medicine, NEJMe1713888. http://doi.org/10.1056/NEJMe1713888

White, G. C., McMillan, C. W., Kingdon, H. S., & Shoemaker, C. B. (1989). Use of Recombinant Antihemophilic Factor in the Treatment of Two Patients with Classic Hemophilia. New England Journal of Medicine, 320(3), 166–170. http://doi.org/10.1056/NEJM198901193200307

Ylä-Herttuala, S. (2012). Endgame: Glybera Finally Recommended for Approval as the First Gene Therapy Drug in the European Union. Molecular Therapy, 20(10), 1831–1832. http://doi.org/10.1038/MT.2012.194




DOI: https://doi.org/10.24114/jbio.v5i3.12472

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