Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B

Pipe, Steven W.; Leebeek, Frank W.G.; Recht, Michael; Key, Nigel S.; Castaman, Giancarlo; Miesbach, Wolfgang; Lattimore, Susan; Peerlinck, Kathelijne; Valk, Paul van der; Coppens, Michiel; Kampmann, Peter; Meijer, Karina; O’Connell, Niamh M; Pasi, John; Hart, Daniel P.; Kazmi, Rashid; Astermark, Jan; Hermans, Cédric; Klamroth, Robert; Lemons, Richard S.; Visweshwar, Nathan; Drygalski, Annette von; Young, Guy; Crary, Shelley E.; Escobar, Miguel A.; Gomez, Esteban; Kruse‐Jarres, Rebecca; Quon, Doris; Symington, Emily; Wang, Michael; Wheeler, Allison P.; Gut, Robert; Liu, Ying P; Dolmetsch, Ricardo; Cooper, David L.; Li, Yanyan; Goldstein, Brahm; Monahan, Paul E.

doi:10.1056/nejmoa2211644

Cited by 166 publications

(155 citation statements)

References 34 publications

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“…Haemophilia B patients can expect to achieve mean endogenous FIX concentrations of approximately 35%, with a limited risk of needing immunosuppressive therapy to control a secondary hepatic reaction 12 and with a prolonged durability of FIX expression of at least 10 years if not more, as recently predicted. 13 The long-term risks for haemophilia A and B are unclear and durability of haemophilia A gene therapy is currently of concern.…”

mentioning

confidence: 69%

“…Uniquely, the licensed gene therapy is also available to patients with severe haemophilia B who have lower levels of pre‐existing antibodies to the adeno‐associated viral vector used to deliver the FIX gene. Haemophilia B patients can expect to achieve mean endogenous FIX concentrations of approximately 35%, with a limited risk of needing immunosuppressive therapy to control a secondary hepatic reaction 12 and with a prolonged durability of FIX expression of at least 10 years if not more, as recently predicted 13 . The long‐term risks for haemophilia A and B are unclear and durability of haemophilia A gene therapy is currently of concern 14,15 …”

Section: Figurementioning

confidence: 96%

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Towards achieving a haemophilia‐free mind

Hermans

Pierce

2023

Haemophilia

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mentioning

confidence: 69%

Section: Figurementioning

confidence: 96%

Towards achieving a haemophilia‐free mind

Hermans

Pierce

2023

Haemophilia

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“…Patients with HB can expect to achieve mean endogenous FIX levels of approximately 35%, with a prolonged durability of FIX expression of at least 10 years. 17,18 Yet, 17% of the patients who received etranacogene dezaparvovec required corticosteroids to control the increase of alanine aminotransferase (ALT) and preserve FIX-expressing hepatocytes. In patients with severe HA treated with valoctogene roxaparvovec, outcome measures at 2 years post-treatment showed a mean of 22 IU/dL increase of FVIII activity compared to baseline and a 84.5% decrease of annualised treated bleeding rate.…”

Section: Discussionmentioning

confidence: 99%

Perspectives and perception of haemophilia gene therapy by French patients

Pietu,

Giraud,

Chamouard

et al. 2023

Haemophilia

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Introduction and aimA national survey was initiated by representatives of French patients with haemophilia (AFH) and the French reference centre for haemophilia, in order to appreciate the awareness and knowledge of these patients regarding haemophilia gene therapy (HGT) and understand better their position about this innovative treatment that will soon become available.ResultsOf 143 answers received, 137 could be analysed, representing about 3.5% of patients with severe or moderate haemophilia over 16year‐old. They were 80.3% with haemophilia A and 19.7 % with haemophilia B, with a severe form of the disease for 80.3 % of them. Curiosity for HGT was formulated by 64.2% of the participants, 33.6 % being interested by this approach as soon as it will be available and 38.7 % preferring to wait until more patients have been treated. Only 3.6 % of the participants would never consider receiving HGT. The level of awareness and knowledge was estimated to be limited by 39.5 % of the patients. More than 60 % of them declared having never or almost never discussed HGT with the team of their haemophilia centre. Before deciding to get HGT, 54.4 % of the participants considered that it will be very important to compare it with their current treatment and 53.7 % would like to be better informed by their care providers.ConclusionsThese results highlight the need for training and education for patients, but also for professionals at haemophilia centres, about HGT and the shared decision‐making process. Objective, unbiased and transparent information must be available for patients about this very promising therapy which nonetheless carries more uncertainty and unknowns compared to other haemophilia treatments.

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“…administration. These have now become commercially available gene therapies, indicated for adult patients affected by hemophilia 14,15 .…”

Section: Mainmentioning

confidence: 99%

Spatio-temporal dynamics of the liver shapes hepatocytes heterogeneity and impacts in vivo gene transfer and editing

Cantore

Starinieri

Milani

et al. 2023

Preprint

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The liver is a central organ for metabolism and hepatocytes are the main cell type responsible for most of its functions. Several previous studies investigated the cell types involved in tissue homeostasis and regeneration1–4, however the mechanisms underlying post-natal liver growth and establishment of the mature hepatocyte phenotypes remain to be fully understood. Here we investigate liver tissue dynamics in mice during growth and adulthood, by spatial transcriptomics5, clonal analysis, and lineage tracing. We observe progressive establishment of metabolic zonation of hepatocytes following weaning, with specification of the centrilobular identity only in adults. We report that only a fraction of hepatocytes proliferates in the newborn liver, generating most of the adult tissue and that preferential genetic modification (either gene transfer or gene editing) of the more proliferating hepatocytes allows expansion of the genetically engineered liver area, stably maintained throughout tissue homeostasis. We also describe age-dependent differences in the efficiency and distribution of lentiviral in vivo gene delivery, with higher efficiency of gene transfer in young compared to adult animals and a skewed localization within the liver lobule. We identify high proteasome activity in the peri-central lobular area as the major determinant of the observed outcome and successfully revert it by proteasomal inhibition before gene transfer. Overall, our findings provide new insights into the spatio-temporal dynamics of the liver during post-natal growth and hepatocyte heterogeneity, which extends our understanding of liver biology and have important implications for therapeutic applications.

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Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B

Cited by 166 publications

References 34 publications

Towards achieving a haemophilia‐free mind

Towards achieving a haemophilia‐free mind

Perspectives and perception of haemophilia gene therapy by French patients

Spatio-temporal dynamics of the liver shapes hepatocytes heterogeneity and impacts in vivo gene transfer and editing

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