The intersection of vector biology, gene therapy, and hemophilia

Lisowski, Leszek; Staber, Janice M.; Wright, J. Fraser; Valentino, Leonard A.

doi:10.1002/rth2.12586

Cited by 16 publications

(34 citation statements)

References 105 publications

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“…Based on the reverse allometric relationship between intracellular GEF and W 0.25 of mammalian specie, the GEFs in dogs and monkeys were expected to be higher than that in humans. However, two bio-engineered AAV capsids Spark100 and Spark200 utilized in SPK-9001 and SPK-8011, respectively, have a higher transduction efficiency for human hepatocytes than natural AAV serotypes 10, 20 . Spark100 and Spark200 capsids were identified by screening a human specific replication competent viral library composed of DNA shuffled AAV capsids with a humanized mouse liver model.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, three immunogenic targets in AAV-mediated gene therapy have been identified and discussed: transgene product (FIX, FVIII, FIX-Pauda, B-domain deleted recombinant FVIII), AAV capsid, and AAV capsid antigens expressed on the surface of transduced cells 10 . Anti-transgene product antibodies (FIX or FVIII inhibitors) have not been reported in hemophilia AAV clinical trials 10 but anti-human FIX or FVIII antibodies were often detected in monkeys and dogs receiving AAV encoding a human transgene product. As shown in Table 2, the vectors encoding human FIX or FVIII (scAAV2/8-LP1-hFIXco, GO-8, BMN270, DTX201 and SPK8011) induced anti-human FIX or FVIII antibodies in dogs or monkeys.…”

Section: Discussionmentioning

confidence: 99%

“…Anti-AAV neutralizing antibodies and AAV capsid specific T cells exist in many people because of prior exposure to the common wide-type virus 10, 22 . AAV capsid antibodies may preclude transduction of AAV vectors and T-cell response may eliminate transduced human hepatocytes 10 . Dose selection for patients with preexisting immunity prior to gene therapy is quite a dilemma.…”

Section: Discussionmentioning

confidence: 99%

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First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

Zou

2022

Preprint

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Rational first-in-patient (FIP) dose selection is critical for successful clinical development of gene therapy. In this study, the author compared the performance of two allometric scaling approaches and body weight-based dose conversion approach for FIP dose prediction for adeno-associated virus (AAV)-mediated hemophilia gene therapy. The performance of the three approaches was examined using preclinical and clinical efficacy data of nine AAV vectors. In general, body weight-based direct conversion of effective doses in monkeys or dogs was more likely to underestimate FIP dose but worked better for one bioengineered vector with a high transduction efficiency specifically in humans. In contrast, allometric scaling between gene efficiency factor (logGEF) and body weight (logW) was likely to overestimate FIP dose but worked better than the other two approaches when vector capsid-specific T-cell responses were detected in patients. The third approach, allometric scaling between logGEF and W-0.25 was appropriate for FIP dose prediction in the absence of T-cell responses to AAV vectors or a dramatic difference in vector transduction efficiency between animals and humans. A decision tree was tentatively proposed to facilitate approach selection for FIP dose prediction in AAV-mediated hemophilia gene therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

Zou

2022

Preprint

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“…5 While not all patients are eligible for AAV-mediated gene transfer, newer methodologies in development such as lentiviral vector-mediated gene therapy, gene editing, lipid nanoparticle-based delivery of factorencoding mRNA, or cell-based gene delivery may offer expanded eligibility and advances in efficacy and safety. [6][7][8][9] Clinical haemophilia gene therapy trials have mainly been sponsored in North America and Europe. Currently, only 12% (26/217) of countries worldwide participate in related trials.…”

Section: Introductionmentioning

confidence: 99%

“…There was no long‐term toxicity given maximum follow‐up times between 2 and 8 years for participants who continue to express factor, or up to 15 years for participants of an earlier trial who lost factor expression 5 . While not all patients are eligible for AAV‐mediated gene transfer, newer methodologies in development such as lentiviral vector‐mediated gene therapy, gene editing, lipid nanoparticle‐based delivery of factor‐encoding mRNA, or cell‐based gene delivery may offer expanded eligibility and advances in efficacy and safety 6–9 …”

Section: Introductionmentioning

confidence: 99%

Haemophilia gene therapy—Update on new country initiatives

et al. 2022

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Introduction Gene therapy is emerging as a potential cure for haemophilia. Gene therapy is a one‐time treatment that can elevate factor levels for many years and minimize or eliminate the need for clotting factor concentrate (CFC) replacement therapy. However, there is a paucity of reports on gene therapy efforts in countries outside of North America or Europe, especially in low‐and‐middle‐income countries (LMIC). All indications are that gene therapy will be one of standard care treatments for haemophilia in the future. Still, it may not be accessible to many countries due to various barriers and challenges. At the same time, each country may formulate solutions that may be used globally. Aim To summarize the approaches taken to establish haemophilia gene therapy in Japan, China, India, South Africa, and Brazil, and to describe the US‐initiated multi‐LMIC haemophilia gene therapy development program to include Peru, Vietnam, Thailand, Nepal, and Sri Lanka. Methods A review of related published information or as accessible by each country's author. Results Different starting conditions, differing input and level of support from the multitude of stakeholders, and strong leadership have led to various approaches for facilitating research and developing needed infrastructure and regulatory and financing models. Gene therapy programs are at various stages of development and include both adeno‐associated viral and lentiviral vectors. Conclusion Global partnerships and collaboration, exchange of knowledge and experience, and alignment of processes across borders will promote further progress towards global access to gene therapy for haemophilia.

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A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment?

Valentino¹,

Ozelo²,

Herzog³

et al. 2023

Journal of Thrombosis and Haemostasis

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The intersection of vector biology, gene therapy, and hemophilia

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 16 publications

References 105 publications

First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling

Haemophilia gene therapy—Update on new country initiatives

A review of the rationale for gene therapy for hemophilia A with inhibitors: one-shot tolerance and treatment?

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