Evolutionary insights into coagulation factor IX Padua and other high-specific-activity variants.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
09 03 2021
09 03 2021
Historique:
received:
07
05
2019
accepted:
20
01
2021
entrez:
3
3
2021
pubmed:
4
3
2021
medline:
1
6
2021
Statut:
ppublish
Résumé
The high-specific-activity factor IX (FIX) variant Padua (R338L) is the most promising transgene for hemophilia B (HB) gene therapy. Although R338 is strongly conserved in mammalian evolution, amino acid substitutions at this position are underrepresented in HB databases. We therefore undertook a complete 20 amino acid scan and determined the specific activity of human (h) and canine (c) FIX variants with every amino acid substituted at position 338. Notably, we observe that hFIX-R338L is the most active variant and cFIX-R338L is sevenfold higher than wild-type (WT) cFIX. This is consistent with the previous identification of hFIX-R338L as a cause of a rare X-linked thrombophilia risk factor. Moreover, WT hFIX and cFIX are some of the least active variants. We confirmed the increased specific activity relative to FIX-WT in vivo of a new variant, cFIX-R338I, after gene therapy in an HB dog. Last, we screened 232 pediatric subjects with thromboembolic disease without identifying F9 R338 variants. Together these observations suggest a surprising evolutionary pressure to limit FIX activity with WT FIX rather than maximize FIX activity.
Identifiants
pubmed: 33656538
pii: S2473-9529(21)00160-9
doi: 10.1182/bloodadvances.2019000405
pmc: PMC7948292
doi:
Substances chimiques
Factor IX
9001-28-9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1324-1332Subventions
Organisme : NHLBI NIH HHS
ID : K08 HL140078
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL064190
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL139420
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL142012
Pays : United States
Informations de copyright
© 2021 by The American Society of Hematology.
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