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A1 - Viral Vectors (excluding AAV – including RNA, adenovirus, herpesvirus, bocavirus, and chimetics)

3: A Recombinant Human Bocavirus Vector Delivers Therapeutic Levels of CTFR to Cystic Fibrosis Primary Human Airway Cells and Transduces Airway Epithelium In Vivo

Type: General Session

Presentation Details
Session Title: Presidential Symposium

Gene therapies for severe pulmonary diseases, including cystic fibrosis (CF) could achieve meaningful clinical outcomes if the physical and cellular barriers of airway epithelial cell transduction could be overcome.  Current viral-based gene delivery approaches are also limited by genome capacity and immunogenicity. Human Bocavirus Type 1 (HBoV1) is a nonpathogenic  parvovirus of genus bocaparvovirus  that readily infects human airway epithelial cells repeatedly in nature and offers 20% extra genomic capacity beyond adeno-associated virus 2 (AAV2).  CBN-1000 is a hybrid viral vector featuring an HBoV1 capsid engineered with conventional AAV2-vector genome elements. The hybrid vector displays exquisite lung tropism while simultaneously leveraging much of the safety, regulatory, and CMC profile of AAV vectors.  In the present study we evaluated the in vivo biodistribution and functional rescue by CBN-1000 in relevant species as well as in patient-derived human airway epithelial cells from two genotypes of cystic fibrosis. Primary human airway basal cells cultured at an air-liquid interface and differentiated into mature human airway epithelial cells were transduced with CBN-1000 carrying CFTR, the gene mutated in CF. Western blot demonstrated restoration of mature CFTR protein equal to that of non-CF cultures, and electrophysiology confirmed rescue of CFTR-mediated ion current. For biodistribution studies, an  124I-labeled HBoV1 capsid was administered intratracheally resulting in similar biodistribution and clearance in both WT and CF ferrets, despite a moderate-to-severe lung disease phenotype in the transgenic animals.  Furthermore, CBN-1000 was well tolerated in both NHP and ferrets at clinically relevant dose levels after pulmonary delivery, and demonstrated airway-specific gene expression.  These data demonstrate that CBN-1000, a new and selective viral vector for lung delivery, can deliver large transgenes including full-length CFTR which is out-of-reach for AAV vectors.  CBN-1000 addresses several of the most daunting challenges of current pulmonary gene delivery and exemplifies the potential of capsids derived from non-AAV, autonomous parvoviruses to expand the scope of gene therapy for diverse applications.

Jeff Moffit, Salvatore Iovino, Graham Casey, Leila Malkoc, Gillian Payne, Josh Merritt, Robert M. Kotin, Marc Abrams, Joel Schneider

Carbon Biosciences, Waltham, MA"

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