Cellular stress and coagulation factor production: when more is not necessarily better

Chen, Zhouji; Herzog, Roland W.; Kaufman, Randal J.

doi:10.1016/j.jtha.2023.10.005

Cited by 2 publications

(1 citation statement)

References 100 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…46 Ectopic expression of FVIII in hepatocytes and its challenging biosynthesis have been proposed to underlie FVIII decline and high incidence of transaminitis in AAV-FVIII vector recipients. 47 These hypotheses have spurred works on biobetter FVIII variants that would fold and secrete better, potentially permitting higher circulating FVIII without increasing vector doses, thus repeating the success seen after the inclusion of FIX-Padua in AAV-FIX vectors. GO-8 study (NCT03001830) employed an AAV8 vector encoding the FVIII-V3 variant, which produced 3-fold higher FVIII levels in preclinical studies, and enrolled 12 participants, who received 6e11, 2e12, 4e12 or 6e12 vg/kg, and most of whom sustained FVIII expression for over 5 years.…”

Section: Emerging Technologiesmentioning

confidence: 99%

Current and emerging gene therapies for haemophilia A and B

Kaczmarek,

Miesbach,

Ozelo

et al. 2024

Haemophilia

View full text Add to dashboard Cite

IntroductionAfter decades of stumbling clinical development, the first gene therapies for haemophilia A and B have been commercialized and have normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several other clinical programs testing adeno‐associated viral (AAV) vector gene therapy are at various stages of clinical testing.DiscussionMultiyear follow‐up in phase 1/2 and 3 studies showed long‐term and sometimes curative but widely variable and unpredictable efficacy. Liver toxicities, mostly low‐grade, occur in the 1st year in at least some individuals in all haemophilia A and B trials and are poorly understood. Wide variability and unpredictability of outcome and slow decline of FVIII levels are a major disadvantage because immune responses to AAV vectors preclude repeat dosing, which otherwise could improve suboptimal or restore declining expression, while overexpression may predispose to thrombosis. Long‐term safety outcomes will need lifelong monitoring because AAV vectors infused at high doses integrate into chromosomes at rates that raise questions about potential oncogenicity and necessitate vigilance. Alternative gene transfer systems employing gene editing and/or non‐viral vectors are under development and promise to overcome some limitations of the current state of the art for both haemophilia A and B.ConclusionsAAV gene therapies for haemophilia have now become new treatment options but not universal cures. AAV is a powerful but imperfect gene transfer platform. Biobetter FVIII transgenes may help solve some problems plaguing gene therapy for haemophilia A. Addressing variability and unpredictability of efficacy, and delivery of gene therapy to ineligible patient subgroups may require different gene transfer systems, most of which are not ready for clinical translation yet but bring innovations needed to overcome the current limitations of gene therapy.

show abstract

Section: Emerging Technologiesmentioning

confidence: 99%