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1.
JAMA ; 331(20): 1707-1708, 2024 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-38696211

RESUMEN

In this narrative medicine essay, a medical ethicist discusses the complexity of juggling the interests of members in online forums dedicated to rare diseases after being blocked upon disclosing her affiliation with a medical school, thus barring her from the support and information she needed to manage her daughter's rare disease.


Asunto(s)
Información de Salud al Consumidor , Enfermedades Genéticas Congénitas , Enfermedades Raras , Apoyo Social , Humanos , Relaciones Médico-Paciente , Enfermedades Genéticas Congénitas/psicología , Enfermedades Genéticas Congénitas/terapia , Enfermedades Raras/psicología , Enfermedades Raras/terapia , Bases de Datos como Asunto , Acceso a la Información , Comunicación , Internet
2.
Life Sci ; 348: 122685, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38710276

RESUMEN

Gene therapy in pediatrics represents a cutting-edge therapeutic strategy for treating a range of genetic disorders that manifest in childhood. Gene therapy involves the modification or correction of a mutated gene or the introduction of a functional gene into a patient's cells. In general, it is implemented through two main modalities namely ex vivo gene therapy and in vivo gene therapy. Currently, a noteworthy array of gene therapy products has received valid market authorization, with several others in various stages of the approval process. Additionally, a multitude of clinical trials are actively underway, underscoring the dynamic progress within this field. Pediatric genetic disorders in the fields of hematology, oncology, vision and hearing loss, immunodeficiencies, neurological, and metabolic disorders are areas for gene therapy interventions. This review provides a comprehensive overview of the evolution and current progress of gene therapy-based treatments in the clinic for pediatric patients. It navigates the historical milestones of gene therapies, currently approved gene therapy products by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for children, and the promising future for genetic disorders. By providing a thorough compilation of approved gene therapy drugs and published results of completed or ongoing clinical trials, this review serves as a guide for pediatric clinicians to get a quick overview of the situation of clinical studies and approved gene therapy products as of 2023.


Asunto(s)
Aprobación de Drogas , Terapia Genética , Pediatría , Humanos , Terapia Genética/métodos , Niño , Pediatría/métodos , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/tratamiento farmacológico , Ensayos Clínicos como Asunto
3.
BMJ Open ; 14(5): e085237, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38760043

RESUMEN

INTRODUCTION: Around 2000 children are born in the UK per year with a neurodevelopmental genetic syndrome with significantly increased morbidity and mortality. Often little is known about expected growth and phenotypes in these children. Parents have responded by setting up social media groups to generate data themselves. Given the significant clinical evidence gaps, this research will attempt to identify growth patterns, developmental profiles and phenotypes, providing data on long-term medical and educational outcomes. This will guide clinicians when to investigate, monitor or treat symptoms and when to search for additional or alternative diagnoses. METHODS AND ANALYSIS: This is an observational, multicentre cohort study recruiting between March 2023 and February 2026. Children aged 6 months up to 16 years with a pathogenic or likely pathogenic variant in a specified gene will be eligible. Children will be identified through the National Health Service and via self-recruitment. Parents or carers will complete a questionnaire at baseline and again 1 year after recruitment. The named clinician (in most cases a clinical geneticist) will complete a clinical proforma which will provide data from their most recent clinical assessment. Qualitative interviews will be undertaken with a subset of parents partway through the study. Growth and developmental milestone curves will be generated through the DECIPHER website (https://deciphergenomics.org) where 5 or more children have the same genetic syndrome (at least 10 groups expected). ETHICS AND DISSEMINATION: The results will be presented at national and international conferences concerning the care of children with genetic syndromes. Results will also be submitted for peer review and publication.


Asunto(s)
Enfermedades Raras , Humanos , Enfermedades Raras/genética , Enfermedades Raras/terapia , Niño , Preescolar , Reino Unido , Lactante , Adolescente , Proyectos de Investigación , Femenino , Masculino , Estudios Observacionales como Asunto , Trastornos del Neurodesarrollo/genética , Estudios de Cohortes , Estudios Multicéntricos como Asunto , Enfermedades Genéticas Congénitas/terapia , Mejoramiento de la Calidad , Padres
4.
Chem Rev ; 124(12): 7976-8008, 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38801719

RESUMEN

Transfer ribonucleic acid (tRNA) therapeutics will provide personalized and mutation specific medicines to treat human genetic diseases for which no cures currently exist. The tRNAs are a family of adaptor molecules that interpret the nucleic acid sequences in our genes into the amino acid sequences of proteins that dictate cell function. Humans encode more than 600 tRNA genes. Interestingly, even healthy individuals contain some mutant tRNAs that make mistakes. Missense suppressor tRNAs insert the wrong amino acid in proteins, and nonsense suppressor tRNAs read through premature stop signals to generate full length proteins. Mutations that underlie many human diseases, including neurodegenerative diseases, cancers, and diverse rare genetic disorders, result from missense or nonsense mutations. Thus, specific tRNA variants can be strategically deployed as therapeutic agents to correct genetic defects. We review the mechanisms of tRNA therapeutic activity, the nature of the therapeutic window for nonsense and missense suppression as well as wild-type tRNA supplementation. We discuss the challenges and promises of delivering tRNAs as synthetic RNAs or as gene therapies. Together, tRNA medicines will provide novel treatments for common and rare genetic diseases in humans.


Asunto(s)
ARN de Transferencia , Humanos , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , ARN de Transferencia/química , Animales , Terapia Genética/métodos , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/genética
5.
J Control Release ; 369: 696-721, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38580137

RESUMEN

Rare genetic diseases, often referred to as orphan diseases due to their low prevalence and limited treatment options, have long posed significant challenges to our medical system. In recent years, Messenger RNA (mRNA) therapy has emerged as a highly promising treatment approach for various diseases caused by genetic mutations. Chemically modified mRNA is introduced into cells using carriers like lipid-based nanoparticles (LNPs), producing functional proteins that compensate for genetic deficiencies. Given the advantages of precise dosing, biocompatibility, transient expression, and minimal risk of genomic integration, mRNA therapies can safely and effectively correct genetic defects in rare diseases and improve symptoms. Currently, dozens of mRNA drugs targeting rare diseases are undergoing clinical trials. This comprehensive review summarizes the progress of mRNA therapy in treating rare genetic diseases. It introduces the development, molecular design, and delivery systems of mRNA therapy, highlighting their research progress in rare genetic diseases based on protein replacement and gene editing. The review also summarizes research progress in various rare disease models and clinical trials. Additionally, it discusses the challenges and future prospects of mRNA therapy. Researchers are encouraged to join this field and collaborate to advance the clinical translation of mRNA therapy, bringing hope to patients with rare genetic diseases.


Asunto(s)
Terapia Genética , ARN Mensajero , Enfermedades Raras , Humanos , Enfermedades Raras/terapia , Enfermedades Raras/genética , ARN Mensajero/administración & dosificación , ARN Mensajero/genética , Animales , Terapia Genética/métodos , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/genética , Nanopartículas , Edición Génica/métodos
7.
Med Law Rev ; 32(2): 178-204, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38513296

RESUMEN

Heritable human genome editing (HHGE) to correct a nuclear gene sequence that would result in a serious genetic condition in a future child is presented as 'treatment' in various ethics and policy materials, and as morally preferable to the 'selection' practice of preimplantation genetic testing (PGT), which is subject to the disability critique. However, whether HHGE is 'treatment' for a future child, or another form of 'selection', or whether HHGE instead 'treats' prospective parents, are now central questions in the debate regarding its possible legalisation. This article argues that the idea of 'treatment' for a future child is largely a proxy for 'seriousness of purpose', intended to distinguish HHGE to avoid serious genetic conditions from less obviously justifiable uses; that HHGE is best understood, and morally justified, as a form of 'treatment' for prospective parents who strongly desire an unaffected genetically related child and who have no, or poor, options to achieve this; that HHGE would be morally permissible if consistent with that child's welfare; that legalisation is supportable with reference to the right to respect for private and family life under Article 8 of the European Convention on Human Rights; and that HHGE is morally distinguishable from PGT.


Asunto(s)
Edición Génica , Diagnóstico Preimplantación , Humanos , Edición Génica/ética , Edición Génica/legislación & jurisprudencia , Diagnóstico Preimplantación/ética , Genoma Humano , Pruebas Genéticas/legislación & jurisprudencia , Pruebas Genéticas/ética , Terapia Genética/ética , Terapia Genética/legislación & jurisprudencia , Enfermedades Genéticas Congénitas/terapia
8.
Mol Genet Metab ; 142(1): 108360, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38428378

RESUMEN

The Mendelian disorders of chromatin machinery (MDCMs) represent a distinct subgroup of disorders that present with neurodevelopmental disability. The chromatin machinery regulates gene expression by a range of mechanisms, including by post-translational modification of histones, responding to histone marks, and remodelling nucleosomes. Some of the MDCMs that impact on histone modification may have potential therapeutic interventions. Two potential treatment strategies are to enhance the intracellular pool of metabolites that can act as substrates for histone modifiers and the use of medications that may inhibit or promote the modification of histone residues to influence gene expression. In this article we discuss the influence and potential treatments of histone modifications involving histone acetylation and histone methylation. Genomic technologies are facilitating earlier diagnosis of many Mendelian disorders, providing potential opportunities for early treatment from infancy. This has parallels with how inborn errors of metabolism have been afforded early treatment with newborn screening. Before this promise can be fulfilled, we require greater understanding of the biochemical fingerprint of these conditions, which may provide opportunities to supplement metabolites that can act as substrates for chromatin modifying enzymes. Importantly, understanding the metabolomic profile of affected individuals may also provide disorder-specific biomarkers that will be critical for demonstrating efficacy of treatment, as treatment response may not be able to be accurately assessed by clinical measures.


Asunto(s)
Cromatina , Redes y Vías Metabólicas , Humanos , Cromatina/genética , Cromatina/metabolismo , Redes y Vías Metabólicas/genética , Histonas/metabolismo , Histonas/genética , Procesamiento Proteico-Postraduccional , Acetilación , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapia , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/metabolismo , Ensamble y Desensamble de Cromatina/genética , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/metabolismo , Recién Nacido , Metilación
9.
Mutagenesis ; 39(3): 157-171, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38332115

RESUMEN

The therapeutic potential of the human genome has been explored through the development of next-generation therapeutics, which have had a high impact on treating genetic disorders. Classical treatments have traditionally focused on common diseases that require repeated treatments. However, with the recent advancements in the development of nucleic acids, utilizing DNA and RNA to modify or correct gene expression in genetic disorders, there has been a paradigm shift in the treatment of rare diseases, offering more potential one-time cure options. Advanced technologies that use CRISPR-Cas 9, antisense oligonucleotides, siRNA, miRNA, and aptamers are promising tools that have achieved successful breakthroughs in the treatment of various genetic disorders. The advancement in the chemistry of these molecules has improved their efficacy, reduced toxicity, and expanded their clinical use across a wide range of tissues in various categories of human disorders. However, challenges persist regarding the safety and efficacy of these advanced technologies in translating into clinical practice. This review mainly focuses on the potential therapies for rare genetic diseases and considers how next-generation techniques enable drug development to achieve long-lasting curative effects through gene inhibition, replacement, and editing.


Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Enfermedades Genéticas Congénitas , Terapia Genética , Enfermedades Raras , Humanos , Enfermedades Raras/genética , Enfermedades Raras/terapia , Edición Génica/métodos , Terapia Genética/métodos , Enfermedades Genéticas Congénitas/terapia , Enfermedades Genéticas Congénitas/genética , Oligonucleótidos Antisentido/uso terapéutico , ARN Interferente Pequeño/uso terapéutico , ARN Interferente Pequeño/genética , MicroARNs/genética , Aptámeros de Nucleótidos/uso terapéutico
10.
Int J Mol Sci ; 24(7)2023 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-37047074

RESUMEN

Nonsense mutations trigger premature translation termination and often give rise to prevalent and rare genetic diseases. Consequently, the pharmacological suppression of an unscheduled stop codon represents an attractive treatment option and is of high clinical relevance. At the molecular level, the ability of the ribosome to continue translation past a stop codon is designated stop codon readthrough (SCR). SCR of disease-causing premature termination codons (PTCs) is minimal but small molecule interventions, such as treatment with aminoglycoside antibiotics, can enhance its frequency. In this review, we summarize the current understanding of translation termination (both at PTCs and at cognate stop codons) and highlight recently discovered pathways that influence its fidelity. We describe the mechanisms involved in the recognition and readthrough of PTCs and report on SCR-inducing compounds currently explored in preclinical research and clinical trials. We conclude by reviewing the ongoing attempts of personalized nonsense suppression therapy in different disease contexts, including the genetic skin condition epidermolysis bullosa.


Asunto(s)
Codón sin Sentido , Enfermedades Genéticas Congénitas , Extensión de la Cadena Peptídica de Translación , Medicina de Precisión , Enfermedades Raras , Supresión Genética , Animales , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Codón sin Sentido/genética , Fibrosis Quística/genética , Fibrosis Quística/terapia , Epidermólisis Ampollosa/genética , Epidermólisis Ampollosa/terapia , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Nefritis Hereditaria/genética , Nefritis Hereditaria/terapia , Degradación de ARNm Mediada por Codón sin Sentido , Extensión de la Cadena Peptídica de Translación/efectos de los fármacos , Medicina de Precisión/métodos , Medicina de Precisión/tendencias , Enfermedades Raras/genética , Enfermedades Raras/terapia , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/terapia , Síndrome de Shwachman-Diamond/genética , Síndrome de Shwachman-Diamond/terapia , Supresión Genética/efectos de los fármacos , Supresión Genética/genética , Terminación de la Cadena Péptídica Traduccional/efectos de los fármacos , Aminoglicósidos/farmacología
11.
Cell ; 186(7): 1302-1304, 2023 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-37001495

RESUMEN

CRISPR-Cas9-based base editing allows precise base editing to achieve conversion of adenosine to guanine or cytosine to thymidine. In this issue of Cell, McAuley et al. use adenine base editing to correct a single base-pair mutation causing human CD3δ deficiency, demonstrating superior efficiency of genetic correction with reduced undesired genetic alterations compared with standard CRISPR-Cas9 editing.


Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Enfermedades del Sistema Inmune , Humanos , Adenina , Sistemas CRISPR-Cas/genética , Terapia Genética , Mutación , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/terapia
12.
Singapore Med J ; 64(1): 7-16, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36722512

RESUMEN

There are more than 7,000 paediatric genetic diseases (PGDs) but less than 5% have treatment options. Treatment strategies targeting different levels of the biological process of the disease have led to optimal health outcomes in a subset of patients with PGDs, where treatment is available. In the past 3 decades, there has been rapid advancement in the development of novel therapies, including gene therapy, for many PGDs. The therapeutic success of treatment relies heavily on knowledge of the genetic basis and the disease mechanism. Specifically, gene therapy has been shown to be effective in various clinical trials, and indeed, these trials have led to regulatory approvals, paving the way for gene therapies for other types of PGDs. In this review, we provide an overview of the treatment strategies and focus on some of the recent advancements in therapeutics for PGDs.


Asunto(s)
Enfermedades Genéticas Congénitas , Niño , Humanos , Enfermedades Genéticas Congénitas/terapia , Terapia Genética
15.
Nature ; 604(7905): 343-348, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35322228

RESUMEN

Gene therapy is a potentially curative medicine for many currently untreatable diseases, and recombinant adeno-associated virus (rAAV) is the most successful gene delivery vehicle for in vivo applications1-3. However, rAAV-based gene therapy suffers from several limitations, such as constrained DNA cargo size and toxicities caused by non-physiological expression of a transgene4-6. Here we show that rAAV delivery of a suppressor tRNA (rAAV.sup-tRNA) safely and efficiently rescued a genetic disease in a mouse model carrying a nonsense mutation, and effects lasted for more than 6 months after a single treatment. Mechanistically, this was achieved through a synergistic effect of premature stop codon readthrough and inhibition of nonsense-mediated mRNA decay. rAAV.sup-tRNA had a limited effect on global readthrough at normal stop codons and did not perturb endogenous tRNA homeostasis, as determined by ribosome profiling and tRNA sequencing, respectively. By optimizing the AAV capsid and the route of administration, therapeutic efficacy in various target tissues was achieved, including liver, heart, skeletal muscle and brain. This study demonstrates the feasibility of developing a toolbox of AAV-delivered nonsense suppressor tRNAs operating on premature termination codons (AAV-NoSTOP) to rescue pathogenic nonsense mutations and restore gene function under endogenous regulation. As nonsense mutations account for 11% of pathogenic mutations, AAV-NoSTOP can benefit a large number of patients. AAV-NoSTOP obviates the need to deliver a full-length protein-coding gene that may exceed the rAAV packaging limit, elicit adverse immune responses or cause transgene-related toxicities. It therefore represents a valuable addition to gene therapeutics.


Asunto(s)
Codón sin Sentido , Dependovirus , Terapia Genética , Adenoviridae , Animales , Codón sin Sentido/genética , Codón de Terminación/genética , Codón de Terminación/metabolismo , Dependovirus/genética , Enfermedades Genéticas Congénitas/terapia , Vectores Genéticos , Humanos , Ratones , Degradación de ARNm Mediada por Codón sin Sentido/genética , ARN de Transferencia/genética , ARN de Transferencia/metabolismo
16.
Life Sci ; 294: 120375, 2022 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-35123997

RESUMEN

Gene therapy is the product of man's quest to eliminate diseases. Gene therapy has three facets namely, gene silencing using siRNA, shRNA and miRNA, gene replacement where the desired gene in the form of plasmids and viral vectors, are directly administered and finally gene editing based therapy where mutations are modified using specific nucleases such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short tandem repeats (CRISPR)/CRISPR-associated protein (Cas)-associated nucleases. Transfer of gene is either through transformation where under specific conditions the gene is directly taken up by the bacterial cells, transduction where a bacteriophage is used to transfer the genetic material and lastly transfection that involves forceful delivery of gene using either viral or non-viral vectors. The non-viral transfection methods are subdivided into physical, chemical and biological. The physical methods include electroporation, biolistic, microinjection, laser, elevated temperature, ultrasound and hydrodynamic gene transfer. The chemical methods utilize calcium- phosphate, DAE-dextran, liposomes and nanoparticles for transfection. The biological methods are increasingly using viruses for gene transfer, these viruses could either integrate within the genome of the host cell conferring a stable gene expression, whereas few other non-integrating viruses are episomal and their expression is diluted proportional to the cell division. So far, gene therapy has been wielded in a plethora of diseases. However, coherent and innocuous delivery of genes is among the major hurdles in the use of this promising therapy. Hence this review aims to highlight the current options available for gene transfer along with the advantages and limitations of every method.


Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Técnicas de Transferencia de Gen , Enfermedades Genéticas Congénitas/terapia , Terapia Genética , Vectores Genéticos/uso terapéutico , Enfermedades Genéticas Congénitas/genética , Humanos
17.
AAPS J ; 24(1): 31, 2022 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-35102450

RESUMEN

Given the recent success of gene therapy modalities and the growing number of cell and gene-based therapies in clinical development across many different therapeutic areas, it is evident that this evolving field holds great promise for the unmet medical needs of patients. The recent approvals of Luxturna® and Zolgensma® prove that recombinant adeno-associated virus (rAAV)-based gene therapy is a transformative modality that enables curative treatment for genetic disorders. Over the last decade, Takeda has accumulated significant experience with rAAV-based gene therapies, especially in the early stage of development. In this review, based on the learnings from Takeda and publicly available information, we aim to provide a guiding perspective on Drug Metabolism and Pharmacokinetics (DMPK) substantial role in advancing therapeutic gene therapy modalities from nonclinical research to clinical development, in particular the characterization of gene therapy product biodistribution, elimination (shedding), immunogenicity assessment, multiple platform bioanalytical assays, and first-in-human (FIH) dose projection strategies. Graphical abstract.


Asunto(s)
Dependovirus/genética , Terapia Genética/métodos , Vectores Genéticos/genética , Animales , Productos Biológicos , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/terapia , Humanos , Proteínas Recombinantes de Fusión/genética
18.
Int J Mol Sci ; 23(2)2022 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-35054919

RESUMEN

Inherited retinal diseases (IRDs) are a leading cause of blindness. To date, 260 disease-causing genes have been identified, but there is currently a lack of available and effective treatment options. Cone photoreceptors are responsible for daylight vision but are highly susceptible to disease progression, the loss of cone-mediated vision having the highest impact on the quality of life of IRD patients. Cone degeneration can occur either directly via mutations in cone-specific genes (primary cone death), or indirectly via the primary degeneration of rods followed by subsequent degeneration of cones (secondary cone death). How cones degenerate as a result of pathological mutations remains unclear, hindering the development of effective therapies for IRDs. This review aims to highlight similarities and differences between primary and secondary cone cell death in inherited retinal diseases in order to better define cone death mechanisms and further identify potential treatment options.


Asunto(s)
Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Predisposición Genética a la Enfermedad , Células Fotorreceptoras Retinianas Conos/metabolismo , Enfermedades de la Retina/genética , Enfermedades de la Retina/metabolismo , Animales , Apoptosis/genética , Autofagia/genética , Biomarcadores , Muerte Celular , Estrés del Retículo Endoplásmico , Estudios de Asociación Genética , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/terapia , Humanos , Estrés Oxidativo , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/terapia , Transducción de Señal
19.
N Engl J Med ; 385(24): 2264-2270, 2021 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-34881838

RESUMEN

Inherited junctional epidermolysis bullosa is a severe genetic skin disease that leads to epidermal loss caused by structural and mechanical fragility of the integuments. There is no established cure for junctional epidermolysis bullosa. We previously reported that genetically corrected autologous epidermal cultures regenerated almost an entire, fully functional epidermis on a child who had a devastating form of junctional epidermolysis bullosa. We now report long-term clinical outcomes in this patient. (Funded by POR FESR 2014-2020 - Regione Emilia-Romagna and others.).


Asunto(s)
Epidermis/trasplante , Epidermólisis Ampollosa de la Unión/terapia , Queratinocitos/trasplante , Transducción Genética , Transgenes , Autorrenovación de las Células , Células Cultivadas/trasplante , Niño , Células Clonales , Epidermis/patología , Epidermólisis Ampollosa de la Unión/genética , Epidermólisis Ampollosa de la Unión/patología , Estudios de Seguimiento , Enfermedades Genéticas Congénitas/patología , Enfermedades Genéticas Congénitas/terapia , Terapia Genética , Vectores Genéticos , Humanos , Queratinocitos/citología , Queratinocitos/fisiología , Masculino , Regeneración , Células Madre/fisiología , Trasplante Autólogo
20.
Int J Mol Sci ; 22(24)2021 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-34948153

RESUMEN

Rare genetic diseases are a group of pathologies with often unmet clinical needs. Even if rare by a single genetic disease (from 1/2000 to 1/more than 1,000,000), the total number of patients concerned account for approximatively 400 million peoples worldwide. Finding treatments remains challenging due to the complexity of these diseases, the small number of patients and the challenge in conducting clinical trials. Therefore, innovative preclinical research strategies are required. The zebrafish has emerged as a powerful animal model for investigating rare diseases. Zebrafish combines conserved vertebrate characteristics with high rate of breeding, limited housing requirements and low costs. More than 84% of human genes responsible for diseases present an orthologue, suggesting that the majority of genetic diseases could be modelized in zebrafish. In this review, we emphasize the unique advantages of zebrafish models over other in vivo models, particularly underlining the high throughput phenotypic capacity for therapeutic screening. We briefly introduce how the generation of zebrafish transgenic lines by gene-modulating technologies can be used to model rare genetic diseases. Then, we describe how zebrafish could be phenotyped using state-of-the-art technologies. Two prototypic examples of rare diseases illustrate how zebrafish models could play a critical role in deciphering the underlying mechanisms of rare genetic diseases and their use to identify innovative therapeutic solutions.


Asunto(s)
Enfermedades Genéticas Congénitas , Modelos Genéticos , Enfermedades Raras , Pez Cebra , Animales , Investigación Biomédica , Modelos Animales de Enfermedad , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Enfermedades Genéticas Congénitas/terapia , Humanos , Enfermedades Raras/genética , Enfermedades Raras/metabolismo , Enfermedades Raras/terapia , Pez Cebra/genética , Pez Cebra/metabolismo
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