BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression.
Adolescent
Adult
Aged
Chemical and Drug Induced Liver Injury
/ etiology
CpG Islands
/ genetics
Factor IX
/ biosynthesis
Gain of Function Mutation
Gene Expression Regulation
Genetic Therapy
Hemophilia B
/ genetics
Humans
Immunity, Innate
Male
Middle Aged
Pathogen-Associated Molecular Pattern Molecules
/ immunology
Prospective Studies
Recombinant Fusion Proteins
/ therapeutic use
Rhabdomyolysis
/ etiology
Toll-Like Receptor 9
/ physiology
Transgenes
Young Adult
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
11 02 2021
11 02 2021
Historique:
received:
23
12
2019
accepted:
20
09
2020
pubmed:
18
10
2020
medline:
2
7
2021
entrez:
17
10
2020
Statut:
ppublish
Résumé
Gene therapy has the potential to maintain therapeutic blood clotting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene into liver cells. This phase 1/2, open-label dose-escalation study investigated BAX 335 (AskBio009, AAV8.sc-TTR-FIXR338Lopt), an adeno-associated virus serotype 8 (AAV8)-based FIX Padua gene therapy, in patients with hemophilia B. This report focuses on 12-month interim analyses of safety, pharmacokinetic variables, effects on FIX activity, and immune responses for dosed participants. Eight adult male participants (aged 20-69 years; range FIX activity, 0.5% to 2.0%) received 1 of 3 BAX 335 IV doses: 2.0 × 1011; 1.0 × 1012; or 3.0 × 1012 vector genomes/kg. Three (37.5%) participants had 4 serious adverse events, all considered unrelated to BAX 335. No serious adverse event led to death. No clinical thrombosis, inhibitors, or other FIX Padua-directed immunity was reported. FIX expression was measurable in 7 of 8 participants; peak FIX activity displayed dose dependence (32.0% to 58.5% in cohort 3). One participant achieved sustained therapeutic FIX activity of ∼20%, without bleeding or replacement therapy, for 4 years; in others, FIX activity was not sustained beyond 5 to 11 weeks. In contrast to some previous studies, corticosteroid treatment did not stabilize FIX activity loss. We hypothesize that the loss of transgene expression could have been caused by stimulation of innate immune responses, including CpG oligodeoxynucleotides introduced into the BAX 335 coding sequence by codon optimization. This trial was registered at www.clinicaltrials.gov as #NCT01687608.
Identifiants
pubmed: 33067633
pii: S0006-4971(21)00265-2
doi: 10.1182/blood.2019004625
pmc: PMC7885820
doi:
Substances chimiques
BAX 335
0
Pathogen-Associated Molecular Pattern Molecules
0
Recombinant Fusion Proteins
0
TLR9 protein, human
0
Toll-Like Receptor 9
0
factor IX-Padua
0
Factor IX
9001-28-9
Banques de données
ClinicalTrials.gov
['NCT01687608']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
763-774Subventions
Organisme : NHLBI NIH HHS
ID : RC3 HL103396
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021 by The American Society of Hematology.
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