Advances in genome editing for genetic hearing loss.
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ABSTRACT:
SUBMITTER: Ding N
PROVIDER: S-EPMC7647959 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Genome editing opens up a new frontier in developing personalized therapeutic solutions. With the unprecedented advance in the discovery and engineering of gene editing nucleases, it has now become potentially feasible to therapeutically influence up to 90% of all human genetic mutations. Hearing loss is one of the most well studied fields from the genetics perspective, with more than one hundred identified deafness genes. Novel viral and non-viral vectors have been established as safe and efficient modalities to deliver transgenes into cells of the cochlea and to the vestibular system in animal models. Recent studies demonstrated proof-of-concept for therapeutic genome and base editing in the mammalian inner ear and preclinical development is ongoing. This review summarizes important advances and future challenges for this transformative therapeutic modality for genetic and non-genetic hearing loss.
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Project description:Hearing plays a crucial role in human development. Receiving and processing sounds are essential for the advancement of the speech ability during the early childhood and for a proper functioning in the society. Hearing loss is one of the most frequent disabilities that affect human senses. It can be caused by genetic or environmental factors or both of them. Calcium- and integrin-binding protein 2 (CIB2) is one of the recently identified genes, involved in HI pathogenesis. CIB2 is widely expressed in various human and animal tissues, mainly in skeletal muscle, nervous tissue, inner ear, and retina. The CIB2 protein is responsible for maintaining Ca2+ homeostasis in cells and interacting with integrins-transmembrane receptors essential for cell adhesion, migration, and activation of signaling pathways. Calcium signaling pathway is crucial for signal transduction in the inner ear, and integrins regulate hair cell differentiation and maturation of the stereocilia. To date, mutations detected in CIB2 are causative for nonsyndromic hearing loss (DFNB48) or Usher syndrome type 1 J. Patients harboring biallelic CIB2 mutations suffer from bilateral, early onset, moderate to profound HI. In the paper, we summarize the current status of the research on CIB2.
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Project description:Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births, with ~50-60% of those related to genetic causes. Technological advances enabled the identification of hundreds of genes related to hearing loss (HL), with important implications for patients, their families, and the community. Despite these advances, in Latin America, the population with hearing loss remains underdiagnosed, with most studies focusing on a single locus encompassing the GJB2/GJB6 genes. Here we discuss how current and emerging genetic knowledge has the potential to alter the approach to diagnosis and management of hearing loss, which is the current situation in Latin America, and the barriers that still need to be overcome.
| S-EPMC10888486 | biostudies-literature
Project description:New technologies have recently emerged that enable targeted editing of genomes in diverse systems. This includes precise manipulation of gene sequences in their natural chromosomal context and addition of transgenes to specific genomic loci. This progress has been facilitated by advances in engineering targeted nucleases with programmable, site-specific DNA-binding domains, including zinc finger proteins and transcription activator-like effectors (TALEs). Recent improvements have enhanced nuclease performance, accelerated nuclease assembly, and lowered the cost of genome editing. These advances are driving new approaches to many areas of biotechnology, including biopharmaceutical production, agriculture, creation of transgenic organisms and cell lines, and studies of genome structure, regulation, and function. Genome editing is also being investigated in preclinical and clinical gene therapies for many diseases.
| S-EPMC3424393 | biostudies-literature
Project description:Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.
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Project description:β-hemoglobinopathies are the most common genetic disorders worldwide and are caused by mutations affecting the production or the structure of adult hemoglobin. Patients affected by these diseases suffer from anemia, impaired oxygen delivery to tissues, and multi-organ damage. In the absence of a compatible donor for allogeneic bone marrow transplantation, the lifelong therapeutic options are symptomatic care, red blood cell transfusions and pharmacological treatments. The last decades of research established lentiviral-mediated gene therapy as an efficacious therapeutic strategy. However, this approach is highly expensive and associated with a variable outcome depending on the effectiveness of the viral vector and the quality of the cell product. In the last years, genome editing emerged as a valuable tool for the development of curative strategies for β-hemoglobinopathies. Moreover, due to the wide range of its applications, genome editing has been extensively used to study regulatory mechanisms underlying globin gene regulation allowing the identification of novel genetic and pharmacological targets. In this work, we review the current advances and challenges of genome editing approaches to β-hemoglobinopathies. Special focus has been directed towards strategies aimed at correcting the defective β-globin gene or at inducing fetal hemoglobin (HbF), which are in an advanced state of clinical development.
| S-EPMC7865242 | biostudies-literature
Project description:Multiple applications of genome editing by CRISPR-Cas9 necessitate stringent regulation and Cas9 variants have accordingly been generated whose activity responds to small ligands, temperature or light. However, these approaches are often impracticable, for example in clinical therapeutic genome editing in situ or gene drives in which environmentally-compatible control is paramount. With this in mind, we have developed heritable Cas9-mediated mammalian genome editing that is acutely controlled by the cheap lysine derivative, Lys(Boc) (BOC). Genetic code expansion permitted non-physiological BOC incorporation such that Cas9 (Cas9BOC) was expressed in a full-length, active form in cultured somatic cells only after BOC exposure. Stringently BOC-dependent, heritable editing of transgenic and native genomic loci occurred when Cas9BOC was expressed at the onset of mouse embryonic development from cRNA or Cas9BOC transgenic females. The tightly controlled Cas9 editing system reported here promises to have broad applications and is a first step towards purposed, spatiotemporal gene drive regulation over large geographical ranges.
| S-EPMC6030211 | biostudies-other
Project description:Sensorineural hearing loss can result from dysfunction of the inner ear, auditory nerve, or auditory pathways in the central nervous system. Sensorineural hearing loss can be associated with age, exposure to ototoxic drugs or noise, or mutations in nuclear or mitochondrial genes. However, it is idiopathic in some patients. Although these disorders are mainly caused by dysfunction of the inner ear, little of the pathophysiology in sensorineural hearing loss is known due to inaccessibility of the living human inner ear for biopsy and pathological analysis. The inner ear has previously been thought of as an immune-privileged organ. We recently showed that a missense mutation of the NLRP3 gene is associated with autosomal-dominant sensorineural hearing loss with cochlear autoinflammation in two unrelated families. NLRP3 encodes the NLRP3 protein, a key component of the NLRP3 inflammasome that is expressed in immune cells, including monocytes and macrophages. Gain-of-function mutations of NLRP3 cause abnormal activation of the NLRP3 inflammasome leading to IL-1β secretion in a spectrum of autosomal dominant systemic autoinflammatory phenotypes termed cryopyrin-associated periodic syndromes. The affected subjects of our two families demonstrated atypical phenotypes compared with those reported for subjects with cryopyrin-associated periodic syndromes. These observations led us to test the hypothesis that macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The inflammasome can indeed be activated in macrophage/monocyte-like cells of the mouse cochlea, with secretion of IL-1β. The macrophage/monocyte-like cells in the cochlea were also found to be associated with hearing loss in a Slc26a4-insufficient mouse model of human deafness. This review addresses our understanding of genetic hearing loss mediated by autoinflammation and macrophage/monocyte-like cells in the cochlea.
| S-EPMC7066252 | biostudies-literature
Project description:Hearing loss is one of the most common concerns for presentation for a geneticist. Presentation prior to the age of one (congenital hearing loss), profound sensorineural hearing loss (SNHL), and bilateral hearing loss are sensitive and should raise concern for genetic causes of hearing loss and prompt referral for genetic testing. Genetic testing particularly in this instance offers the opportunity for anticipatory guidance including possible course of the hearing loss over time and also connection and evaluation for additional congenital anomalies that may be associated with an underlying syndrome vs. isolated genetic hearing loss.
| S-EPMC8020033 | biostudies-literature
Project description:In the age of targeted genomic enrichment and massively parallel sequencing, there is no more efficient genetic testing method for the diagnosis of hereditary hearing loss. More clinical tests are on the market, which can make choosing good tests difficult.More and larger comprehensive genetic studies in patients with hearing loss have been published recently. They remind us of the importance of looking for both single nucleotide variation and copy number variation in all genes implicated in nonsyndromic hearing loss. They also inform us of how a patient's history and phenotype provide essential information in the interpretation of genetic data.Choosing the most comprehensive genetic test improves the chances of a genetic diagnosis and thereby impacts clinical care.
| S-EPMC5241053 | biostudies-literature