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

Valentino, Leonard A.; Ozelo, Margareth C.; Herzog, Roland W.; Key, Nigel S.; Pishko, Allyson M.; Ragni, Margaret V.; Samelson-Jones, Ben; Lillicrap, David

doi:10.1016/j.jtha.2023.05.011

Cited by 9 publications

(4 citation statements)

References 95 publications

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“… 39 The immune tolerance induced by AAV gene therapy in the real-world setting further supports the rationale of studying gene therapy in human HA patients with inhibitors. 40 Notably, tolerance induction in PC3 took nearly 2 years and so patience as well as careful hemostatic management in the interim between vector administration and detectable FVIII activity may be necessary in translational approaches.…”

Section: Discussionmentioning

confidence: 99%

AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life

Doshi,

Samelson-Jones,

Nichols

et al. 2024

Molecular Therapy - Methods & Clinical Development

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Section: Discussionmentioning

confidence: 99%

AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life

Doshi,

Samelson-Jones,

Nichols

et al. 2024

Molecular Therapy - Methods & Clinical Development

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“…(C) Gene augmentation therapies: EMA/FDA have approved "classical" gene therapies, i.e., those involving vector-based transfer of the protein-coding cDNA sequence into the patient, for monogenic disorders. These include the hemophilias [236][237][238][239][240][241][242], homozygous hypercholesterolemia [243], and others. Very recently, entirely different approaches towards gene augmentation are being developed which are based on highly specific modulation of RNA-based regulatory networks [244,245].…”

Section: Current Status Of Translational Research Into Nucleic Acids-...mentioning

confidence: 99%

“…Despite complex biotechnological challenges, current lack of efficient therapies for multiple severe and abundant diseases is clear evidence for the need to proceed beyond current options. Reassuringly, a remarkable number of pioneering clinical trials have proven technical and clinical feasibility of nucleic acid therapeutic approaches for important cardiovascular [108, and hematological [236][237][238][239][240][241][242] diseases. These are truly fundamental achievements compared to the situation one decade ago.…”

Section: Current Status Of Translational Research Into Nucleic Acids-...mentioning

confidence: 99%

Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets—Recent Insights at Molecular and Cellular Level

Poller,

Sahoo,

Hajjar

et al. 2023

Cells

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While it is well known that 98–99% of the human genome does not encode proteins, but are nevertheless transcriptionally active and give rise to a broad spectrum of noncoding RNAs [ncRNAs] with complex regulatory and structural functions, specific functions have so far been assigned to only a tiny fraction of all known transcripts. On the other hand, the striking observation of an overwhelmingly growing fraction of ncRNAs, in contrast to an only modest increase in the number of protein-coding genes, during evolution from simple organisms to humans, strongly suggests critical but so far essentially unexplored roles of the noncoding genome for human health and disease pathogenesis. Research into the vast realm of the noncoding genome during the past decades thus lead to a profoundly enhanced appreciation of the multi-level complexity of the human genome. Here, we address a few of the many huge remaining knowledge gaps and consider some newly emerging questions and concepts of research. We attempt to provide an up-to-date assessment of recent insights obtained by molecular and cell biological methods, and by the application of systems biology approaches. Specifically, we discuss current data regarding two topics of high current interest: (1) By which mechanisms could evolutionary recent ncRNAs with critical regulatory functions in a broad spectrum of cell types (neural, immune, cardiovascular) constitute novel therapeutic targets in human diseases? (2) Since noncoding genome evolution is causally linked to brain evolution, and given the profound interactions between brain and immune system, could human-specific brain-expressed ncRNAs play a direct or indirect (immune-mediated) role in human diseases? Synergistic with remarkable recent progress regarding delivery, efficacy, and safety of nucleic acid-based therapies, the ongoing large-scale exploration of the noncoding genome for human-specific therapeutic targets is encouraging to proceed with the development and clinical evaluation of novel therapeutic pathways suggested by these research fields.

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“…Valoctocogene roxaparvovec, etranacogene dezaparvovec and fidanacogene elaparvovec are approved for use only in adults without factor inhibitors [ 10 – 13 , 17 ]. Animal models suggest that AAV-based gene therapy for haemophilia A has the potential for induction of immune tolerance to FVIII [ 18 ]. Of note, a study evaluating valoctocogene roxaparvovec in patients with severe haemophilia A and FVIII inhibitors is in the recruitment stage (NCT04684940) [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

A 360-degree perspective on adeno-associated virus (AAV)-based gene therapy for haemophilia: Insights from the physician, the nurse and the patient

Miesbach,

Mulders,

Breederveld

et al. 2024

Orphanet J Rare Dis

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Background Adeno-associated virus (AAV)-based gene therapy for haemophilia has advanced substantially in the last 13 years; recently, three products have received approvals from regulatory authorities. Although the impact on quality of life seems promising, some limitations remain, such as the presence of pre-existing anti-AAV neutralising antibodies and the occurrence of hepatotoxicity. This review follows the CSL Behring-sponsored symposium at the 27th Congress of the European Hematology Association (EHA) 2022 that examined the haemophilia gene therapy process from a 360-degree multidisciplinary perspective. Here, the faculty (haematologist, nurse and haemophilia patient) summarised their own viewpoints from the symposium, with the aim of highlighting the key considerations required to engage with gene therapy effectively, for both patients and providers, as well as the importance of multidisciplinary collaboration, including with industry. Results When considering these new therapies, patients face a complex decision-making process, which includes whether gene therapy is right for them at their current stage of life. The authors agreed that collaboration and tailored education across the multidisciplinary team (including patients and their carers/families), starting early in the process and continuing throughout the long-term follow-up period, is key for the success of gene therapy. Additionally, patient expectations, which may surround eligibility, follow-up requirements and treatment outcomes, should be continually explored. During these ongoing discussions, transparent communication of the unknown factors, such as anticipated clotting factor levels, long-term factor expression and safety, and psychological changes, is critical. To ensure efficiency and comprehensiveness, clearly‑defined protocols should outline the whole process, which should include the recording and management of long-term effects. Conclusion In order to engage effectively, both patients and providers should be familiar with these key considerations prior to their involvement with the haemophilia gene therapy process. The future after the approval of haemophilia gene therapies remains to be seen and real-world evidence is eagerly awaited.

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

Cited by 9 publications

References 95 publications

AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life

AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life

Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets—Recent Insights at Molecular and Cellular Level

A 360-degree perspective on adeno-associated virus (AAV)-based gene therapy for haemophilia: Insights from the physician, the nurse and the patient

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