Lentiviral expression of wildtype LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa.

Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
29 Feb 2024
Historique:
received: 21 08 2023
revised: 26 01 2024
accepted: 27 02 2024
medline: 2 3 2024
pubmed: 2 3 2024
entrez: 2 3 2024
Statut: aheadofprint

Résumé

The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the Ear, Nose and Throat department of a tertiary pediatric hospital linked to the United Kingdom's National EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants in laminin subunit alpha-3 (LAMA3) were found in 10/15 patients where genotype was available. LAMA3 encodes a subunit of the laminin-332 heterotrimeric extracellular matrix protein complex and is expressed by airway epithelial basal stem cells. We investigated the benefit of restoring wildtype LAMA3 expression in primary EB patient-derived basal cell cultures. EB basal cells demonstrated weak adhesion to cell culture substrates, but could otherwise be expanded similarly to non-EB basal cells. In vitro lentiviral overexpression of LAMA3A in EB basal cells enabled them to differentiate in air-liquid interface cultures, producing cilia with normal ciliary beat frequency. Moreover, transduction restored cell adhesion to levels comparable to a non-EB donor culture. These data provide proof-of-concept for a combined cell and gene therapy approach to treat airway disease in LAMA3-affected EB.

Identifiants

DOI: 10.1016/j.ymthe.2024.02.032 PMID: 38429928
pubmed: 38429928
pii: S1525-0016(24)00101-1
doi: 10.1016/j.ymthe.2024.02.032
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Auteurs

Chun Hang Lau (CH)

Epithelial Cell Biology in ENT Research (EpiCENTR) Group, UCL Great Ormond Street Institute of Child Health, University College London, 20c Guilford Street, London, WC1N 1DZ, U.K.

Maral J Rouhani (MJ)

Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London, 5 University Street, London, WC1E 6JF, U.K.; Ear, Nose and Throat Department, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Elizabeth F Maughan (EF)

Epithelial Cell Biology in ENT Research (EpiCENTR) Group, UCL Great Ormond Street Institute of Child Health, University College London, 20c Guilford Street, London, WC1N 1DZ, U.K.; Ear, Nose and Throat Department, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Jessica C Orr (JC)

Epithelial Cell Biology in ENT Research (EpiCENTR) Group, UCL Great Ormond Street Institute of Child Health, University College London, 20c Guilford Street, London, WC1N 1DZ, U.K.; Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London, 5 University Street, London, WC1E 6JF, U.K.

Krishna K Kolluri (KK)

Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London, 5 University Street, London, WC1E 6JF, U.K.

David R Pearce (DR)

UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, U.K.

Elizabeth Haughey (E)

Infection, Immunity and Inflammation Department, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, U.K.

Liam Sutton (L)

Ear, Nose and Throat Department, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Sam Flatau (S)

Ear, Nose and Throat Department, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Pablo Lopez Balboa (PL)

Department of Dermatology, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Maria Laura Bageta (ML)

Department of Dermatology, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Christopher O'Callaghan (C)

Infection, Immunity and Inflammation Department, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, U.K.

Claire M Smith (CM)

Infection, Immunity and Inflammation Department, UCL Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, U.K.

Sam M Janes (SM)

Lungs for Living Research Centre, UCL Respiratory, Division of Medicine, University College London, 5 University Street, London, WC1E 6JF, U.K.

Richard Hewitt (R)

Ear, Nose and Throat Department, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Gabriela Petrof (G)

Department of Dermatology, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

Anna E Martinez (AE)

Department of Dermatology, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.

John A McGrath (JA)

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, Guy's Hospital, St Thomas Street, London, SE1 9RT, U.K.

Colin R Butler (CR)

Epithelial Cell Biology in ENT Research (EpiCENTR) Group, UCL Great Ormond Street Institute of Child Health, University College London, 20c Guilford Street, London, WC1N 1DZ, U.K.; Ear, Nose and Throat Department, Great Ormond Street Hospital NHS Foundation Trust, London, WC1N 3JH, U.K.. Electronic address: rob.hynds@ucl.ac.uk.

Robert E Hynds (RE)

Epithelial Cell Biology in ENT Research (EpiCENTR) Group, UCL Great Ormond Street Institute of Child Health, University College London, 20c Guilford Street, London, WC1N 1DZ, U.K.; UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6DD, U.K.. Electronic address: rob.hynds@ucl.ac.uk.

Classifications MeSH