Current landscape of cystic fibrosis gene therapy

被引:0
|
作者
Plasschaert, Lindsey W. [1 ]
MacDonald, Kelvin D. [2 ,3 ]
Moffit, Jeffrey S. [2 ]
机构
[1] Plasschaert Consulting, Cambridge, MA USA
[2] Carbon Biosci, Waltham, MA 95648 USA
[3] Oregon Hlth & Sci Univ, Dept Pediat, Portland, OR 97239 USA
关键词
cystic fibrosis; CFTR; gene therapy; viral vector; airway; transduction; TRANSMEMBRANE CONDUCTANCE REGULATOR; STRUCTURAL LUNG-DISEASE; ADENOASSOCIATED VIRUS; IN-VITRO; AEROSOL DELIVERY; CLEARANCE INDEX; DOUBLE-BLIND; AAV-CFTR; R-DOMAIN; PHASE-I;
D O I
10.3389/fphar.2024.1476331
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cystic fibrosis is a life-threatening disease that is caused by mutations in CFTR, a gene which encodes an ion channel that supports proper function of several epithelial tissues, most critically the lung. Without CFTR, airway barrier mechanisms are impaired, allowing for chronic, recurrent infections that result in airway remodeling and deterioration of lung structure and function. Small molecule modulators can rescue existing, defective CFTR protein; however, they still leave a subset of people with CF with no current disease modifying treatments, aside from lung transplantation. Gene therapy directed to the lung is a promising strategy to modify CF disease in the organ most associated with morbidity and mortality. It is accomplished through delivery of a CFTR transgene with an airway permissive vector. Despite more than three decades of research in this area, a lung directed gene therapy has yet to be realized. There is hope that with improved delivery vectors, sufficient transduction of airway cells can achieve therapeutic levels of functional CFTR. In order to do this, preclinical programs need to meet a certain level of CFTR protein expression in vitro and in vivo through improved transduction, particularly in relevant airway cell types. Furthermore, clinical programs must be designed with sensitive methods to detect CFTR expression and function as well as methods to measure meaningful endpoints for lung structure, function and disease. Here, we discuss the current understanding of how much and where CFTR needs to be expressed, the most advanced vectors for CFTR delivery and clinical considerations for detecting CFTR protein and function in different patient subsets.
引用
收藏
页数:15
相关论文
共 50 条
  • [21] Current Status and Future Directions of Gene and Cell Therapy for Cystic Fibrosis
    Uta Griesenbach
    Eric W. F. W. Alton
    BioDrugs, 2011, 25 : 77 - 88
  • [22] Current Status and Future Directions of Gene and Cell Therapy for Cystic Fibrosis
    Griesenbach, Uta
    Alton, Eric W. F. W.
    BIODRUGS, 2011, 25 (02) : 77 - 88
  • [23] Gene therapy for the treatment of cystic fibrosis
    Burney, Tabinda J.
    Davies, Jane C.
    APPLICATION OF CLINICAL GENETICS, 2012, 5 : 29 - 36
  • [24] Airway gene therapy and cystic fibrosis
    Parsons, DW
    JOURNAL OF PAEDIATRICS AND CHILD HEALTH, 2005, 41 (03) : 94 - 96
  • [25] Prospects for gene therapy for cystic fibrosis
    Davies, JC
    Geddes, DM
    Alton, EWFW
    MOLECULAR MEDICINE TODAY, 1998, 4 (07): : 292 - 299
  • [26] Gene therapy research for cystic fibrosis
    Coutelle, C
    JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION, 1996, 21 (01) : 72 - 74
  • [27] Gene and cell therapy for cystic fibrosis
    Davies, Jane C.
    PAEDIATRIC RESPIRATORY REVIEWS, 2006, 7 : S163 - S165
  • [28] Cystic fibrosis (CF) gene therapy
    Bellon, G
    PEDIATRIC PULMONOLOGY, 1997, : 278 - 279
  • [29] Prospects for gene therapy in cystic fibrosis
    Jaffé, A
    Bush, A
    Geddes, DM
    Alton, EWFW
    ARCHIVES OF DISEASE IN CHILDHOOD, 1999, 80 (03) : 286 - 289
  • [30] Advances in cystic fibrosis gene therapy
    Griesenbach, U
    Geddes, DM
    Alton, EWFW
    CURRENT OPINION IN PULMONARY MEDICINE, 2004, 10 (06) : 542 - 546