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Gene Therapy For Cystic Fibrosis


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Gene Therapy For Cystic Fibrosis

  1. 1. Gene Therapy for the Treatment of Cystic Fibrosis <br />Stephanie M. Delgado<br />RISE Program<br />BIOL 3095<br />
  2. 2. Cystic Fibrosis<br />Autosomal recessive genetic disorder<br />CFTR gene<br />
  3. 3. Gene Therapy<br />What is gene therapy?<br />Objective<br />
  4. 4. Degree of correction required<br />Minimal percentage of cells with a non-CF phenotyperequired to normalize the functions of the CF bronchial epithelial layer.<br />
  5. 5. Barriers for gene delivery<br />Defense mechanisms<br />Delivery systems<br />
  6. 6. Vectors<br />Vectors<br /><ul><li>Target: Airway Epithelium
  7. 7. Objective: Generation of a functional protein</li></li></ul><li>Vectors<br />Viral vectors<br /><ul><li>Adenoviral
  8. 8. Adeno-associated
  9. 9. Lentivirus
  10. 10. Poxvirus, Sendai, Herpes virus </li></li></ul><li>Vectors<br />Non-viral vectors<br /><ul><li>Synthetic vectors
  11. 11. Less likely to induce immune response</li></li></ul><li>Clinical studies<br />Routes<br />Trial Design<br /><ul><li> Adenovirus vectors
  12. 12. AAV vectors
  13. 13. Non-viral vectors</li></ul>Results<br />
  14. 14. Conclusions<br />New design of clinical trials<br />New vectors<br />Gene therapy for CF is still a great hope more than a reality<br />
  15. 15. References<br />Buckley SMK , Howe SJ, Sheard V, Ward NJ, Coutelle C, Thrasher AJ, Waddington SN,      McKay TR. 2008. Lentiviral transduction of the murine lung provides efficient pseudotype and developmental stage-dependent cell-specific transgene expression. Gene Therapy 15: 1167–1175 <br />Conese M, Boyd C, Di Gioia S, Auriche C, Ascenzioni F. 2007. Genomic Context Vectors and Artificial Chromosomes for Cystic Fibrosis Gene Therapy. Current Gene Therapy 7: 175-187 <br />Dannhoffer L, Blouquit-Laye S, Regnier A, Chinet T. 2009. Functional Properties of Mixed Cystic Fibrosis and Normal Bronchial Epithelial Cell Cultures. American Journal of Respiratory Cell and Molecular Biology 40: 717–723. <br />Davies JC. 2006. Gene and cell therapy for cystic fibrosis. Paediatric Respiratory Reviews 7(1):S163-S165. <br />Eubanks M. 2001. Gene Therapy for CF. Environmental Health Perspectives 109: A16 <br />Ferrari S,  Griesenbach U, Iida A, Farley R, Wright AM, Zhu J, Munkonge FM, Smith SN, You J, Ban H, Inoue M, Chan M, Singh C, Verdon B, Argent BE, Wainwright B, Jeffery PK, Geddes DM, Porteous DJ, Hyde SC, Gray MA, Hasegawa M, Alton EW. 2007. Sendai virus-mediated CFTR gene transfer to the airway epithelium. Gene Therapy 14: 1371–1379. <br />Griesenbach U, Alton EW. 2007. Progress and Prospects: Gene Therapy Clinical Trials (Part 1). Gene Therapy 14: 1439–1447. <br />Griesenbach U, Eric WF. 2008. Gene transfer to the lung: Lessons learned from more than 2 decades of CF gene therapy. Advanced Drug Delivery Reviews 61: 128–139. <br />Hyde SC, Pringle IA, Abdullah S, Lawton AE, Davies L, Varathalingam A, Nunez-Alonso G, Green A, Bazzani RP, Sumner-Jones SG, Chan M, Li H, Yew NS, Cheng SH,  Boyd C, Davies JC, Griesenbach U, Porteous DJ, Sheppard DN, Munkonge FM, Walton EW, Gill DR. CpG-free plasmids confer reduced inflammation and sustained pulmonary gene expression. 2008. Nature Biotechnology 26: 549-551 <br />Liu X, Luo M, Guo C, Yan Z, Wang Y, Engelhardt JF. 2007. Comparative biology of rAAV transduction in ferret, pig and human airway epithelia. Gene Therapy 14: 1543–1548. <br />O’Sullivan BP, Freedman SD. 2009. Cystic fibrosis. Lancet 373: 1891–904 <br />Ostrowski LE, Yin W, Diggs PS, Rogers TD, O’Neal WK, Grubb BR. 2007. Expression of CFTR from a ciliated cell-specific promoter is ineffective at correcting nasal potential difference in CF mice. Gene Therapy 14: 1492–1501 <br />Price AR, Limberis MP, Wilson JM, Diamond SL. 2007.  Pulmonary delivery of adenovirus vector formulated with dexamethasone–spermine facilitates homologous vector re-administration. Gene Therapy 14: 1594–1604. <br />Rogers CS, Hao Y, Rokhlina T, Samuel M. 2008. Production of CFTR-null and CFTR-[Delta]F508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer. Journal of Clinical Investigation 118 (4): 1571-1577 <br />Sumner-Jones SG, Davies LA, Varathalingam A, Gill DR, Hyde SC. 2006. Long-term persistence of gene expression from adeno-associated virus serotype 5 in the mouse airways. Gene Therapy 13: 1703–1713. <br />Yu Z, McKay K, Asperen P, Zheng M, Fleming J, Ginn SL, Kizana E, Latham M, Feneley M, Kirkland PD, Rowe P, Lumbers ER, Alexander IE. 2007. Lentivirus vector-mediated gene transfer to the developing bronchiolar airway epithelium in the fetal lamb. The Journal of Gene Medicine 9: 429–439. <br />Ziady AG, Davis PB. 2006. Current prospects for gene therapy of cystic fibrosis. Current Opinion in Pharmacology 6(5):515-521. <br />