SP-101, A Novel Adeno-Associated Virus Gene Therapy for the Treatment of Cystic Fibrosis, Mediates Functional Correction of Primary Human Airway Epithelia From Donors with Cystic Fibrosis

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Although CF affects multiple organs, lung disease is the main cause of morbidity and mortality, and gene therapy is expected to provide a mutation-agnostic option for treatment...

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Bibliographic Details
Published in:	Human gene therapy Vol. 35; no. 17-18; p. 695
Main Authors:	Excoffon, Katherine J D A, Lin, Shen, Narayan, Poornima Kotha Lakshmi, Sitaraman, Sneha, Jimah, Awal M, Fallon, Tyler T, James, Melane L, Glatfelter, Matthew R, Limberis, Maria P, Smith, Mark D, Guffanti, Guia, Kolbeck, Roland
Format:	Journal Article
Language:	English
Published:	United States 01-09-2024
Subjects:	Cells, Cultured Cystic Fibrosis - genetics Cystic Fibrosis - therapy Cystic Fibrosis Transmembrane Conductance Regulator - genetics Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Dependovirus - genetics Doxorubicin - pharmacology Epithelial Cells - metabolism Genetic Therapy - methods Genetic Vectors - administration & dosage Genetic Vectors - genetics Humans Respiratory Mucosa - metabolism Transduction, Genetic gene therapy human airway epithelia adeno-associated virus cystic fibrosis doxorubicin HCl
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Summary:	Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Although CF affects multiple organs, lung disease is the main cause of morbidity and mortality, and gene therapy is expected to provide a mutation-agnostic option for treatment. SP-101 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a human minigene, , and is being investigated as an inhalation treatment for people with CF. To further understand SP-101 activity, studies were performed in human airway epithelia (HAE) derived from multiple CF and non-CF donors. SP-101 restored CFTR-mediated chloride conductance, measured via Ussing chamber assay, at a multiplicity of infection (MOI) as low as 5E2 in the presence of doxorubicin, a small molecule known to augment AAV transduction. Functional correction of CF HAE increased with increasing MOI and doxorubicin concentration and correlated with increasing cell-associated vector genomes and mRNA expression. Tropism studies using a fluorescent reporter vector and single-cell mRNA sequencing of SP-101-mediated mRNA demonstrated broad expression in all cell types after apical transduction, including secretory, ciliated, and basal cells. In summary, SP-101, particularly in combination with doxorubicin, shows promise for a novel CF treatment strategy and strongly supports continued development.
ISSN:	1557-7422
DOI:	10.1089/hum.2024.063