Gene Therapy Approaches for the Treatment of Hemophilia B

Soroka, Anastasiia B.; Feoktistova, Sofia G.; Mityaeva, Olga; Volchkov, Pavel

doi:10.3390/ijms241310766

Cited by 12 publications

(5 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…56 Liver-specific promoter (LP1) was successfully used to develop AAV-based therapeutics to treat factor IX (FIX) deficiency in haemophilia B patients (Hemgenix). 57,58 Another hybrid LP was implemented in an AAV expression cassette delivering B domain depleted human FVIII gene (ROCTAVIAN).…”

Section: Modifications Of Genetic Regulatory Elements Of Aav Expressi...mentioning

confidence: 99%

Optimization strategies and advances in the research and development of AAV‐based gene therapy to deliver large transgenes

Kolesnik,

Nurtdinov,

Oloruntimehin

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

Adeno‐associated virus (AAV)‐based therapies are recognized as one of the most potent next‐generation treatments for inherited and genetic diseases. However, several biological and technological aspects of AAV vectors remain a critical issue for their widespread clinical application. Among them, the limited capacity of the AAV genome significantly hinders the development of AAV‐based gene therapy. In this context, genetically modified transgenes compatible with AAV are opening up new opportunities for unlimited gene therapies for many genetic disorders. Recent advances in de novo protein design and remodelling are paving the way for new, more efficient and targeted gene therapeutics. Using computational and genetic tools, AAV expression cassette and transgenic DNA can be split, miniaturized, shuffled or created from scratch to mediate efficient gene transfer into targeted cells. In this review, we highlight recent advances in AAV‐based gene therapy with a focus on its use in translational research. We summarize recent research and development in gene therapy, with an emphasis on large transgenes (>4.8 kb) and optimizing strategies applied by biomedical companies in the research pipeline. We critically discuss the prospects for AAV‐based treatment and some emerging challenges. We anticipate that the continued development of novel computational tools will lead to rapid advances in basic gene therapy research and translational studies.

show abstract

Section: Modifications Of Genetic Regulatory Elements Of Aav Expressi...mentioning

confidence: 99%

Optimization strategies and advances in the research and development of AAV‐based gene therapy to deliver large transgenes

Kolesnik,

Nurtdinov,

Oloruntimehin

et al. 2024

Clinical & Translational Med

View full text Add to dashboard Cite

show abstract

“…One gene therapy for hemophilia B using liver-directed vectors based on adenoassociated virus (AAV) is approved (etranacogene dezaparvovec), while fidanacogene elaparvovec is in late stage clinical development. 76 Although FIX gene therapy benefits from straightforward and noninvasive administration and the potential for long-term stable plasma FIX levels approaching those in people without hemophilia, some patients express low levels of FIX requiring exogenous factor replacement. [76][77][78][79] Furthermore, there is no way of switching off expression and several questions still need to be answered: what happens in people who develop an antibody reaction to the AAV vector?…”

Section: Future Role Of Ehl Prophylaxismentioning

confidence: 99%

“…76 Although FIX gene therapy benefits from straightforward and noninvasive administration and the potential for long-term stable plasma FIX levels approaching those in people without hemophilia, some patients express low levels of FIX requiring exogenous factor replacement. [76][77][78][79] Furthermore, there is no way of switching off expression and several questions still need to be answered: what happens in people who develop an antibody reaction to the AAV vector? What are the long-term consequences of immunosuppression used to manage adverse effects arising from vector integration?…”

Section: Future Role Of Ehl Prophylaxismentioning

confidence: 99%

Recombinant factor IX Fc for the treatment of hemophilia B

Ljung,

Matino,

Shapiro

2024

European J of Haematology

View full text Add to dashboard Cite

Current hemophilia B treatment guidelines recommend routine prophylaxis with factor IX (FIX) replacement products, tailored to maintain plasma activity at levels that will prevent bleeds. However, plasma FIX activity may not be the primary determinant or best indicator of hemostatic efficacy due to its extravascular distribution. FIX replacement therapy has evolved to include extended half‐life (EHL) products that provide effective bleed protection when administered at intervals of 7 days or longer. rFIXFc is a recombinant fusion protein with an extended circulation time. rFIXFc has a biodistribution profile consistent with distribution into extravascular space, where it may support hemostasis at sites of vessel injury independent of circulating plasma activity levels. The safety and efficacy of rFIXFc prophylaxis is well established in adults, adolescents and children including previously untreated patients with hemophilia B, with substantial evidence from clinical trials and real‐world clinical practice. This review describes the pharmacokinetic characteristics of rFIXFc, summarizes available safety and efficacy data, and evaluates the use of rFIXFc in special populations. Current hemophilia B treatment challenges, including target FIX plasma levels, perioperative use, and management of patients with comorbidities, are discussed together with the potential role of EHL products in the future treatment landscape of hemophilia B.

show abstract

“…These are Glybera (treatment of familial lipoprotein lipase deficiency), approved by the EMA in 2012 [8], but removed from the market in 2017; Luxturna (treatment of Leber's congenital amaurosis type 2 (RPE65)), approved in 2017 (https://www.chop.edu/ treatments/gene-therapy-inherited-retinal-dystrophy-luxturna accessed on 20 November 2023, [9]); Zolgensma (treatment of spinal muscular atrophy (SMA1)), approved in 2019 [10]; Hemgenix (treatment of hemophilia B), approved in 2022 (FDA) and in 2023 (EMA) [11]; Roctavian (treatment of hemophilia A), also approved in 2022 [11]; Upstaza (treatment of severe aromatic L-amino acid decarboxylase (AADC) deficiency), approved by the EMA in 2022 ( [12], https://ir.ptcbio.com/node/15111/pdf accessed on 20 November 2023) and probably approved by the FDA in December 2023; and Elevidys (treatment of Duchenne muscular dystrophy), approved by the FDA in 2023 (https://investorrelations.sarepta. com/node/22736/pdf accessed on 20 November 2023).…”

Section: Introductionmentioning

confidence: 99%

Development of Stable Packaging and Producer Cell Lines for the Production of AAV Vectors

Merten

2024

Microorganisms

View full text Add to dashboard Cite

Today, recombinant adeno-associated virus (rAAV) vectors represent the vector systems which are mostly used for in vivo gene therapy for the treatment of rare and less-rare diseases. Although most of the past developments have been performed by using a transfection-based method and more than half of the authorized rAAV-based treatments are based on transfection process, the tendency is towards the use of stable inducible packaging and producer cell lines because their use is much more straightforward and leads in parallel to reduction in the overall manufacturing costs. This article presents the development of HeLa cell-based packaging/producer cell lines up to their use for large-scale rAAV vector production, the more recent development of HEK293-based packaging and producer cell lines, as well as of packaging cell lines based on the use of Sf9 cells. The production features are presented in brief (where available), including vector titer, specific productivity, and full-to-empty particle ratio.

show abstract

Gene Therapy Approaches for the Treatment of Hemophilia B

Cited by 12 publications

References 75 publications

Optimization strategies and advances in the research and development of AAV‐based gene therapy to deliver large transgenes

Optimization strategies and advances in the research and development of AAV‐based gene therapy to deliver large transgenes

Recombinant factor IX Fc for the treatment of hemophilia B

Development of Stable Packaging and Producer Cell Lines for the Production of AAV Vectors

Contact Info

Product

Resources

About