Hemophilia gene therapy: first, do no harm

Valentino, Leonard A.; Kaczmarek, Radosław; Pierce, Glenn F.; Noone, Declan; O’Mahony, Brian; Page, David; Rotellini, Dawn; Skinner, Mark W

doi:10.1016/j.jtha.2023.06.016

Cited by 17 publications

(3 citation statements)

References 88 publications

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“…In addition, a number of uncertainties 21 and unknowns remain regarding the individual response of each patient, still unpredictable, the long-term efficacy and risks, notably the potential oncogenicity of these drugs. 22 Gene therapy for haemophilia is completely different from that applied in other indications such as spinal muscular atrophy (SMA) which represents the most frequent monogenic cause of childhood mortality 23 or Duchenne muscular dystrophy, diseases without any alternative treatment where vital prognosis is conditioned by the efficacy of the gene therapy.…”

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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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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“…(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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What is a cure through gene therapy? An analysis and evaluation of the use of “cure”

Baas,

Meijer,

Bredenoord

et al. 2024

Med Health Care and Philos

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The development of gene therapy has always come with the expectation that it will offer a cure for various disorders, of which hemophilia is a paradigm example. However, although the term is used regularly, it is unclear what exactly is meant with “cure”. Therefore, the aim of this paper is to analyse how the concept of cure is used in practice and evaluate which of the interpretations is most suitable in discussions surrounding gene therapy. We analysed how cure is used in four different medical fields where the concept raises discussion. We show that cure can be used in three different ways: cure as normalization of the body, cure as obtaining a normal life, or cure as a change in identity. We argue that since cure is a practical term, its interpretation should be context-specific and the various uses can exist simultaneously, as long as their use is suitable to the function the notion of cure plays in each of the settings. We end by highlighting three different settings in the domain of hemophilia gene therapy in which the term cure is used and explore the function(s) it serves in each setting. We conclude that in the clinical application of gene therapy, it could be better to abandon the term cure, whereas more modest and specified definitions of cure are required in the context of health resource allocation decisions and decisions on research funding.

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Hemophilia gene therapy: first, do no harm

Cited by 17 publications

References 88 publications

Perspectives and perception of haemophilia gene therapy by French patients

Perspectives and perception of haemophilia gene therapy by French patients

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

What is a cure through gene therapy? An analysis and evaluation of the use of “cure”

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