Gene therapy

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Therapy based on correcting at the genetic material level a disease process. Three such therapies were marked in the USA in 2017, two CAR-T therapies and one to treat retinal dystrophy due to RPE65 gene variants. As of 2018 over 700 gene therapy products are in development.


Basic considerations

A gene therapy approach requires a profound understanding of a genetic condition. This depth of knowledge is potentially greater than even those specialising in clinical genetics will hold and is likely to involve teams of highly trained professionals many of whom will have technical skills that will need directing in the context of the difficult ethical decisions involved:

  1. Does a characterised mutation lead to either:
    • Loss of function causing a disease
    • Gain of function causing a disease
  2. Does the gene product affect cell survival or development
  3. Does the gene product have tissue specificity.

It then becomes a matter of deciding where it is most appropriate to intervene in cellular mechanisms between the genotype and the ultimate phenotype. Some times this will be dictated by what is possible when the phenotype manifests itself.


  1. Promote the expression of a(n unmutated) gene
  2. Modify messenger RNA to avoid the consequencies of gene expression
  3. Inhibit the expression of a (mutated) gene
  4. Repair the gene
  5. Over express a gene
    • Example use of heat shock protein production mediated by gene expression from adenovirus vector to destroy solid tumours[11]

Some Technologies


  1. Ren SP, Wang L, Wang H, Wu B, Han Y, Wang LS, Wu CT. Gene therapy for human nasopharyngeal carcinoma by adenovirus-mediated transfer of human p53, GM-CSF, and B7-1 genes in a mouse xenograft tumor model. Cancer biotherapy & radiopharmaceuticals. 2008 Oct; 23(5):591-602.(Link to article – subscription may be required.)
  2. Campos SK, Barry MA. Current advances and future challenges in Adenoviral vector biology and targeting. Current gene therapy. 2007 Jun; 7(3):189-204.
  3. Nathwani AC, Tuddenham EGD, Rangarajan S, et al. Adenovirus-associated virus vector–mediated gene transfer in hemophilia B. N Engl J Med 2011. DOI: 10.1056/NEJMoa1108046
  4. Ramsubir S, Nonaka T, Girbés CB, Carpentier S, Levade T, Medin JA. In vivo delivery of human acid ceramidase via cord blood transplantation and direct injection of lentivirus as novel treatment approaches for Farber disease. Molecular genetics and metabolism. 2008 Nov; 95(3):133-41.(Link to article – subscription may be required.)
  5. Abdelmaksoud HE, Yau EH, Zuker M, Sullivan JM. Development of lead hammerhead ribozyme candidates against human rod opsin mRNA for retinal degeneration therapy. Experimental eye research. 2008 Dec 6.(Epub ahead of print) (Link to article – subscription may be required.)
  6. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science (New York, N.Y.). 2000 Apr 28; 288(5466):669-72.
  7. Hacein-Bey-Abina S, Le Deist F, Carlier F, Bouneaud C, Hue C, De Villartay JP, Thrasher AJ, Wulffraat N, Sorensen R, Dupuis-Girod S, Fischer A, Davies EG, Kuis W, Leiva L, Cavazzana-Calvo M. Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. The New England journal of medicine. 2002 Apr 18; 346(16):1185-93.(Link to article – subscription may be required.)
  8. Gaspar HB, Parsley KL, Howe S, King D, Gilmour KC, Sinclair J, Brouns G, Schmidt M, Von Kalle C, Barington T, Jakobsen MA, Christensen HO, Al Ghonaium A, White HN, Smith JL, Levinsky RJ, Ali RR, Kinnon C, Thrasher AJ. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped gammaretroviral vector. Lancet. 2004 Dec 18-31; 364(9452):2181-7.(Link to article – subscription may be required.)
  9. 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, Dal Cortivo L, 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. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. The Journal of clinical investigation. 2008 Sep; 118(9):3132-42.(Link to article – subscription may be required.)
  10. Aiuti A, Slavin S, Aker M, Ficara F, Deola S, Mortellaro A, Morecki S, Andolfi G, Tabucchi A, Carlucci F, Marinello E, Cattaneo F, Vai S, Servida P, Miniero R, Roncarolo MG, Bordignon C. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science (New York, N.Y.). 2002 Jun 28; 296(5577):2410-3.(Link to article – subscription may be required.)
  11. Li JL, Liu HL, Zhang XR, Xu JP, Hu WK, Liang M, Chen SY, Hu F, Chu DT. A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients. Gene therapy. 2008 Dec 18.(Epub ahead of print) (Link to article – subscription may be required.)