Valoctocogene Roxaparvovec and Etranacogene Dezaparavovec: Novel Gene Therapies for Hemophilia A and B

Dougherty, John A.; Dougherty, Kristiann M.

doi:10.1177/10600280231202247

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…Research and development strategies over the past decades have focused on novel EHL concentrates and non‐factor therapeutics for the treatment of haemophilia as well as gene therapy 11,12,33–36 . EHL products utilizing molecular modifications to the FVIII or FIX protein to prolong circulatory half‐life have been successful in decreasing the frequency of infusions in HB to once every 1−2 weeks.…”

Section: Discussionmentioning

confidence: 99%

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Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Meeks,

Zimowski

2024

Haemophilia

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IntroductionThe advent of therapeutic recombinant factor VIII (FVIII) and factor IX (FIX) protein infusions revolutionized the care of persons with haemophilia in the 1990s. It kicked off an era with the increasing use of prophylactic factor infusions for patients and transformed conversations around the ideal trough activity levels as well as the ultimate goals in tailored, individualized care. Our knowledge surrounding the immunologic basis of inhibitor development and treatment derives from a time when patients were receiving frequent factor infusions and focused on immune tolerance induction following inhibitor development.DiscussionMore recently, care was revolutionized again in haemophilia A with the approval of emicizumab, a bispecific antibody mimicking activated FVIII function, to prevent bleeding. The use of emicizumab prophylaxis has resulted in a significantly slower accumulation of factor exposure days and continued effective prophylaxis in the case of inhibitor development. While emicizumab is effective at reducing the frequency of bleeding events in patients with haemophilia A, management of breakthrough bleeds, trauma, and surgeries still requires additional treatment. Ensuring that FVIII is a therapeutic option, particularly for life‐threatening bleeding events and major surgeries is critical to optimizing the care of persons with haemophilia A. Other novel non‐factor concentrate therapies, including rebalancing agents, will dramatically change the landscape for persons with haemophilia B with inhibitors.ConclusionThis review discusses the changing landscape regarding the timing of inhibitor development and management strategies after inhibitor development, stressing the importance of education across the community to continue to vigilantly monitor for inhibitors and be prepared to treat persons with inhibitors.

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Section: Discussionmentioning

confidence: 99%

“…11,12,[33][34][35][36] EHL products utilizing molecular modifications to the FVIII or FIX protein to prolong circulatory…”

mentioning

confidence: 99%

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Meeks,

Zimowski

2024

Haemophilia

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“…Recombinant AAV virus is a leading delivery vector of gene therapies and has been widely used in over 250 clinical trials (see (Shen et al, 2022) for meta-analysis). Seven different rAAV gene therapies have reached the market; Roctavian TM (BioMarin) for treatment of haemophilia A and Hemgenix® (uniQure/CSL) for haemophilia B (Dougherty & Dougherty, 2023), Elevidys® (Sarepta Therapeutics) to treat Duchenne muscular dystrophy (Hoy, 2023), Luxturna TM (Spark Therapeutics Inc) for treatment of retinal dystrophy (Askou et al, 2021), Zolgensma® (Novartis Gene Therapies) for spinal muscular atrophy (Waldrop et al, 2020), Glybera® (Uniqure) to treat lipoprotein lipase deficiency (although it is no longer marketed)…”

Section: Discussionmentioning

confidence: 99%

Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia

Cossins,

Kozma,

Canzonetta

et al. 2024

Preprint

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Congenital myasthenic syndromes (CMS) are a group of inherited disorders characterised by defective neuromuscular transmission and fatigable muscle weakness. Mutations in DOK7, a gene encoding a post-synaptic protein crucial in the formation and stabilisation of the neuromuscular junction (NMJ), rank among the leading three prevalent causes of CMS in diverse populations globally. The majority of DOK7 CMS patients experience varying degrees of disability despite receiving optimised treatment, necessitating the development of improved therapeutic approaches. Here we executed a dose escalation pre-clinical trial using a DOK7-CMS mouse model to assess the efficacy of Amp-101, an innovative AAV gene replacement therapy. Amp-101 is based on AAVrh74 and contains human DOK7 cDNA under the control of a muscle-restricted promoter. We show that at doses 6x1013vg/kg and 1x1014 vg/kg, Amp-101 generated enlarged NMJs and rescued the very severe phenotype of the model. Treated mice became at least as strong as WT littermates and the diaphragm and tibialis anterior muscles displayed robust expression of DOK7. This data suggests that Amp-101 is a promising candidate to move forward to clinic trials.

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Adeno-Associated Virus 5 Protein Particles Produced by E. coli Cell-Free Protein Synthesis

Deuker,

Asilonu,

Bracewell

et al. 2024

ACS Synth. Biol.

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Recombinant adeno-associated viruses (rAAVs) have emerged as important tools for gene therapy and, more recently, vaccine development. Nonetheless, manufacturing can be costly and time-consuming, emphasizing the importance of alternative production platforms. We investigate the potential of E. coli-based cell-free protein synthesis (CFPS) to produce recombinant AAV5 virus-like particles (VLPs). AAV5 virus protein 3 (VP3) constructs, both with and without Strep-tag II, were expressed with CFPS. Lower reaction temperatures resulted in increased solubility, with the untagged variant containing nearly 90% more soluble VLP VP3 protein at 18 °C than at 37 °C. Affinity chromatography of N-terminally Strep(II)-tagged VP3 enabled successful isolation with minimal processing. DLS and TEM confirmed the presence of ∼20 nm particles. Furthermore, the N-terminally tagged AAV5 VP3 VLPs were biologically active, successfully internalizing into HeLa cells. This study describes an innovative approach to AAV VLP production using E. coli-based CFPS, demonstrating its potential for rapid and biologically active AAV VLP synthesis.

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Valoctocogene Roxaparvovec and Etranacogene Dezaparavovec: Novel Gene Therapies for Hemophilia A and B

Cited by 4 publications

References 29 publications

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Haemophilia in the era of novel therapies: Where do inhibitors feature in the new landscape?

Dose escalation pre-clinical trial of novel DOK7-AAV in mouse model of DOK7 congenital myasthenia

Adeno-Associated Virus 5 Protein Particles Produced by E. coli Cell-Free Protein Synthesis

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