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A high efficient FV...
A high efficient FVIII variant corrects bleeding in hemophilia A mouse model
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Mashausi, Dhahiri Saidi (författare)
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Roy, Debmalya (författare)
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- Mangukiya, Hitesh, Researcher (författare)
- Uppsala universitet,Neuroonkologi och neurodegeneration
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Merugu, Siva Bharath (författare)
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Raza, Ghulam (författare)
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Yunus, Fakhar-Un-Nisa (författare)
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Liu, Guo-Song (författare)
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Negi, Hema (författare)
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Li, Dawei (författare)
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(creator_code:org_t)
- Elsevier, 2022
- 2022
- Engelska.
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier. - 0006-291X .- 1090-2104. ; 637, s. 358-364
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Hemophilia A is a bleeding disorder caused by quantitative or qualitative deficiencies in coagulation factor VIII (FVIII). Low FVIII expression due to its unstable mRNA and binding with immunoglobulin-binding protein (BiP) compromises gene therapy endeavors in hemophilia A. Site-directed mutagenesis have demonstrated an improvement in the expression of FVIII proteins. In this study, a targeted point mutation of Pro at position 290 to Thr (P290T) enhances the in vitro specific activity of B-domain-deleted factor VIII (BDD-FVIII). Hydrodynamic gene delivery of P290T cDNA into FVIII-deficient (FVIII-/-) mice corrected bleeding symptoms. P290T variant resulted in high plasma FVIII coagulant activity 24 h post-gene delivery. Furthermore, bleeding time and average blood loss was significantly reduced in FVIII-/- mice injected with P290T variant, whereas BDD-FVIII and PBS-injected mice experienced prolonged bleeding and excessive blood loss. Histological analysis of the liver biopsies revealed no apparent signs of liver damage. No signs of potential toxicity were seen in mice following mice bodyweights assessment. Altogether, our results demonstrate that the introduction of P290T mutation increases both in vitro and in vivo FVIII coagulant activity, supporting ongoing efforts to develop more effective replacement therapy for hemophilia A.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Nyckelord
- Bleeding
- Factor VIII
- Hemophilia A
- Hydrodynamic gene delivery
- Site-directed mutagenesis
- Molecular Biotechnology
- Molekylär bioteknik
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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