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Gene Therapy for the Treatment of Cystic Fibrosis Stephanie M. Delgado RISE Program BIOL 3095

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Page 1: Gene Therapy For Cystic Fibrosis

Gene Therapy for the Treatment of Cystic Fibrosis

Stephanie M. Delgado

RISE ProgramBIOL 3095

Page 2: Gene Therapy For Cystic Fibrosis

Cystic Fibrosis Autosomal recessive genetic

disorder CFTR gene

Page 3: Gene Therapy For Cystic Fibrosis

Gene Therapy

What is gene therapy? Objective

Page 4: Gene Therapy For Cystic Fibrosis

Degree of correction required

Minimal percentage of cells with a non-CF phenotype required to normalize the functions of the CF bronchial epithelial layer.

Page 5: Gene Therapy For Cystic Fibrosis

Barriers for gene delivery Defense mechanisms Delivery systems

Page 6: Gene Therapy For Cystic Fibrosis

Vectors Vectors

Target: Airway EpitheliumObjective: Generation of a functional protein

Page 7: Gene Therapy For Cystic Fibrosis

Vectors Viral vectors

AdenoviralAdeno-associatedLentivirusPoxvirus, Sendai, Herpes virus

Page 8: Gene Therapy For Cystic Fibrosis

Vectors

Non-viral vectorsSynthetic vectorsLess likely to induce immune response

Page 9: Gene Therapy For Cystic Fibrosis

Clinical studies

Routes Trial Design

Adenovirus vectorsAAV vectorsNon-viral vectors

Results

Page 10: Gene Therapy For Cystic Fibrosis

Conclusions

New design of clinical trials New vectors Gene therapy for CF is still a great

hope more than a reality

Page 11: Gene Therapy For Cystic Fibrosis

References

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

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

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.

Davies JC. 2006. Gene and cell therapy for cystic fibrosis. Paediatric Respiratory Reviews 7(1):S163-S165. Eubanks M. 2001. Gene Therapy for CF. Environmental Health Perspectives 109: A16 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.

Griesenbach U, Alton EW. 2007. Progress and Prospects: Gene Therapy Clinical Trials (Part 1). Gene Therapy 14: 1439–1447. 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. 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

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.

O’Sullivan BP, Freedman SD. 2009. Cystic fibrosis. Lancet 373: 1891–904 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 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. 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 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. 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.

Ziady AG, Davis PB. 2006. Current prospects for gene therapy of cystic fibrosis. Current Opinion in Pharmacology 6(5):515-521.


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