Evidence map›Paper›PMID 42380600›Full record

ArticleGene therapy2026

Improving the precision of AAV lung gene therapy for SP-B deficiency using computationally derived lung-specific promoters.

Nicole Zielinska, Erin L Howard, Brenna A Y Stevens, Melanie M Goens, Elena S B Campbell, Madison E Hughes, Yanlong Pei, Liqun Xu, Adithya Achuthan, Arul Vadivel and 11 more

Abstract read
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In one paragraph

Article in Gene therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

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0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

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5 · Who and what money

Authors and funding

21 authors.

Nicole ZielinskaDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Erin L HowardDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Brenna A Y StevensDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Melanie M GoensDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Elena S B CampbellDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Madison E HughesDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Yanlong PeiDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Liqun XuOttawa Hospital Research Institute, Ottawa, ON, Canada.
Adithya AchuthanOttawa Hospital Research Institute, Ottawa, ON, Canada.
Arul VadivelOttawa Hospital Research Institute, Ottawa, ON, Canada.
Arnold ApostolDivision of Nephrology, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, ON, Canada.
Xiaolin HeDivision of Nephrology, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, ON, Canada.
Dinghai ZhengAsimov, Boston, MA, USA.
D Benjamin GordonAsimov, Boston, MA, USA.
Raja R SrinivasAsimov, Boston, MA, USA.
Alec A K NielsenAsimov, Boston, MA, USA.
Jeff L CaswellDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada.
Luis G ArroyoDepartment of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
Darren A YuenDivision of Nephrology, St. Michael's Hospital, Unity Health Toronto and University of Toronto, Toronto, ON, Canada.
Bernard ThebaudOttawa Hospital Research Institute, Ottawa, ON, Canada.
Sarah K WoottonDepartment of Pathobiology, University of Guelph, Guelph, ON, Canada. kwootton@uoguelph.ca.ORCID 0000-0002-5985-2406

Funding

Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology) PJT-166009
6 · The paper itself

Abstract

Recombinant adeno-associated virus (rAAV) platforms have achieved significant success in clinical gene therapy; however, many still rely on ubiquitous promoters. This robust and widespread transgene expression can cause off-target effects, immune activation, and systemic toxicity, limiting their suitability for diseases requiring tissue-specific expression, such as surfactant protein B (SP-B) deficiency. Here, we aimed to improve the precision of AAV-lung gene therapy by evaluating computationally predicted lung-specific promoters with AAV6.2FF, a capsid with strong lung tropism. Promoter strength and specificity were assessed following administration of AAV6.2FF encoding the human placental alkaline phosphatase (AP) reporter gene in mice. Cross-species activity was evaluated in precision-cut lung slices (PCLS) from ferrets and pigs. We identified promoter 5979 as lung-specific in mice, outperforming the ubiquitous CASI promoter (comprised of the cytomegalovirus enhancer, chicken β-actin promoter, and ubiquitin C regulatory elements) in transgene expression and specificity, independent of AAV capsid or route of administration. In a conditional SP-B knockout model, AAV6.2FF-5979-hSPB extended survival in SP-B-deficient mice and outperformed its CASI-driven counterpart. Promoter 5979 exhibited the highest activity among the four synthetic promoters in ferret PCLS, but demonstrated limited activity in pig PCLS, underscoring species-specific differences. This study demonstrates the therapeutic value of tissue-specific promoters in targeted gene therapy while emphasizing the importance of refining algorithmic prediction platforms to ensure reliable cross-species and clinical performance.

Indexed as

DependovirusGenetic TherapyLungPromoter Regions, GeneticPulmonary Surfactant-Associated Protein BAlkaline PhosphataseAnimalsFerretsGene Therapy AgentsGenetic VectorsGPI-Linked ProteinsHumansIsoenzymesMiceMice, KnockoutSwineAlkaline Phosphatasealkaline phosphatase, placentalGPI-Linked ProteinsIsoenzymesPulmonary Surfactant-Associated Protein B

Identifiers

PMID42380600

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.