otoferlin deficiency
Otoferlin Deficiency In Zebrafish Results In Defects In Balance And Hearing: Rescue Of The … As we enter a new era of precision gene therapies, it’s Academia.edu no longer supports Internet Explorer. Otoferlin, a six-C2 domain transmembrane protein linked to deafness in humans, is hypothesized to play a role in exocytosis at hair cell ribbon synapses. Genetic testing can diagnose otoferlin deficiency and other causes of hearing loss—yet it’s not widely done. We also established a critical cGMP manufacturing and development relationship with Catalent,” said Laurence Reid, Ph.D., Chief Executive Officer of Decibel. Further, otoferlin morphants had uninflated swim bladders. Otoferlin regulates release of neurotransmitter from synaptic vesicles during the encoding of sound, and mutations in otoferlin have been linked to deafness in human patients. Several otoferlin C2 domains bind to Ca2+, phospholipids, and proteins. 2015 Jan 12. pii: MCB.01439-14. To date however, otoferlin has been studied almost exclusively in mouse models, and no rescue experiments have been reported. “Beyond DB-OTO, we remain encouraged by the progress in our gene … Genetic testing can diagnose otoferlin deficiency and other causes of hearing loss—yet it’s not widely done. Similar to dysferlin and myoferlin, otoferlin has a FerA domain and its FerA domain has been shown to interact with zwitterionic lipids in a calcium-dependent manner and with negatively charged lipids in a calcium-independent manner. The estimated charge of FerA domain among ferlin proteins varies significantly. Otoferlin Deficiency In Zebrafish Results In Defects In Balance And Hearing: Rescue Of The Balance And Hearing Phenotype With Full-length And Truncated Forms Of Mouse Otoferlin. Dr. Pantginis said the company is planning to target hearing loss associated with monogenic and non-monogenic disorders, starting with otoferlin deficiency, followed by clarin 1 and gap junction protein beta 2 gene deficiencies. 2. DB-OTO is an AAV-based dual-vector gene therapy product candidate designed to selectively express functional OTOF in the inner hair cells of individuals with OTOF deficiency with the goal of enabling the ear to transmit sound to the brain and facilitate hearing. We also established a critical cGMP manufacturing and development relationship with Catalent," said Laurence Reid, Ph.D., Chief Executive Officer of Decibel. Calcium/otoferlin enables t-SNAREs, which have not been preassembled into heterodimers, to drive membrane fusion. Immunofluorescence microscopy reveals localization to both apical and basolateral regions of hair cells. GJB2 encodes the connexin 26 gap junction protein, which is expressed in non-sensory cells of the inner ear such as supporting cells. Mutations in this gene are a cause of neurosensory nonsyndromic recessive deafness, DFNB9. Here we describe the phenotype associated with morpholino induced otoferlin knockdown in zebrafish, and report the results of rescue experiments conducted with full length and truncated forms of otoferlin. In Vitro and In Vivo Analyses of Dual Vector Otoferlin Expression to Support the Clinical Development of AK-OTOF (AAVAnc80-hOTOF Vector) Presenting Author: Eva Andres-Mateos. The NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Rescue experiments conducted with mouse otoferlin restored hearing, balance and inflation of the swim bladder. Deafness-Causing Protein Deficiency Makes Brain Rewire Itself, Research Suggests. Understanding the molecular mechanisms through which otoferlin … Otoferlin Deficiency In Zebrafish Results In Defects In Balance And Hearing: Rescue Of The Balance And Hearing Phenotype With Full-length And Truncated Forms Of Mouse Otoferlin Chatterjee, P., Padmanarayana, M., Abdullah, N., Holman, C. L., LaDu, J., Tanguay, R. L., & Johnson, C. P. (2015). In the second half of 2019, Sensorion launched two preclinical gene therapy programs aiming at correcting hereditary monogenic forms of deafness including Usher Type 1 and deafness caused by a mutation of the gene encoding for Otoferlin. Otoferlin Deficiency In Zebrafish Results In Defects In Balance And Hearing: Rescue Of The Balance And Hearing Phenotype With Full-length And Truncated Forms Of Mouse Otoferlin. 1001 Summerton Way Sorry, preview is currently unavailable. Excitatory postsynaptic currents (EPSCs) recorded from type I spiral ganglion neurons (SGNs) show remarkable variability in amplitude and shape. Otoferlin deficiency in zebrafish results in defects in balance and hearing: rescue of the balance and hearing phenotype with full-length and truncated forms of mouse otoferlin. Mutations in the otoferlin gene are linked to severe congenital hearing loss, a common type of deafness in which patients can hear almost nothing. About the Program: AAV.103 is being designed to restore hearing to individuals with a GJB2 deficiency, the most common cause of congenital hearing loss. In early 2021, we announced encouraging preclinical results on our lead gene therapy program, DB-OTO, for the treatment of people with otoferlin deficiency. To test whether the prolonged spiking activity during TH deficiency may be transmitted at IHC synapses, capacitance measurements were performed in parallel to analysis of otoferlin expression, a protein thought to play an essential role in exocytosis of IHCs. Syt1 deficiency specifically abolishes the fast component of the exocytic burst (Voets et al., 2001), which remained absent despite overexpression of otoferlin (Fig. To date however, otoferlin has been studied almost exclusively in mouse models, and no rescue experiments have been reported. "Other" targets: ncRNA, repeated elements, etc. Objectives: Otoferlin deficiency secondary to biallelic mutations of the OTOF gene causes permanent congenital auditory neuropathy deafness. We find that expression of otoferlin occurs early in development, and is restricted to hair cells and the midbrain. : (541) 929-7840 | Fax: (541) 929-7841Contact Us, Chatterjee P, Padmanarayana M, Abdullah N, Holman CL, LaDu J, Tanguay RL, Johnson CP, Mol Cell Biol. Popular. 6 hours 12 hours 1 day 3 days all. Here we present a mutation analysis and a genotype–phenotype correlation study on the gene encoding otoferlin (OTOF), responsible for the DFNB9 subtype of prelingual hearing impairment. otoferlin directly interacts with SNAP-25 and syntaxin-1B. 3/10/2020 0 Comments CORVALLIS, Ore. – The brains of people with congenital deafness may be rewiring themselves in ways that affect how those people learn, suggesting a need to develop new teaching techniques tailored toward those who have never been able to hear. This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. The most common genetic cause of auditory neuropathy is insufficient production of a protein called otoferlin, which is expressed in cochlear inner hair cells and enables communication with the auditory nerve. Both dysferlin and myoferlin have seven C2 domains. (A) Fusion assays were conducted using reconstituted syntaxin 1 and synaptobrevin 2 vesicles in the presence of 15 µM soluble SNAP-25 and 4 µM otoferlin. Gap junction channels are … Published in Nature … We also established a … Date. http://mcb.asm.org/content/early/2015/01/08/MCB.01439-14.abstract, Morpholino History, Production, and Properties, Custom Morpholinos, Controls and End Modifications, Morpholinos blocking mRNA localization elements. Knockdown of otoferlin results in hearing and balance defects, as well as locomotion deficiencies. In early 2021, we announced encouraging preclinical results on our lead gene therapy program, DB-OTO, for the treatment of people with otoferlin deficiency. [Epub ahead of print]. Chatterjee P, Padmanarayana M, Abdullah N, Holman CL, LaDu J, Tanguay RL, Johnson CP. (B) Either half of otoferlin, C2ABC, or C2DEF was sufficient to accelerate membrane fusion using soluble … Gene Tools, LLC As we enter a new era of precision gene therapies, it’s crucial to expand access to genetic testing so families can understand the reason for their child’s congenital hearing loss and seek out relevant clinical trials. 5C). Development of an AAV-Based Gene Therapy for Children With Congenital Hearing Loss Due to Otoferlin Deficiency (DB-OTO) Adam Palermo ARO Annual Midwinter Meeting February 23, 2021. Connexins are a family of transmembrane proteins that form channels between adjacent cells. Currently, it is unclear how otoferlin controls neurotransmitter release, and the large size of otoferlin prohibits gene therapy. Sensorion’s OTOF-GT gene therapy development program aims to restore hearing in people living with Otoferlin deficiency, one of the most common forms of congenital deafness. Ca2+ influx and subsequent neurotransmitter release at inner hair cell (IHC) active zones govern sound encoding at the first auditory synapse. Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin Conclusion: Low Ca 2 promotes interactions among otoferlin C2C, C2D, C2E, and C2F; high Ca 2 drives t-SNARE and lipid interactions. Otoferlin deficiency in zebrafish results in defects in balance and hearing: rescue of the balance and hearing phenotype with full-length and truncated forms of mouse otoferlin. Development of an AAV-Based Gene Therapy for Children With Congenital Hearing Loss Due to Otoferlin Deficiency (DB-OTO) 1. Enter the email address you signed up with and we'll email you a reset link. Otoferlin Deficiency In Zebrafish Results In Defects In Balance And Hearing: Rescue Of The Balance And Hearing Phenotype With Full-length And Truncated Forms Of Mouse Otoferlin. Otoferlin, a six-C2 domain transmembrane protein linked to deafness in humans, is hypothesized to play a role in exocytosis at hair cell ribbon synapses. Dual-AAV transduction of Otof-/-IHCs fully restored fast exocytosis, while otoferlin-dependent vesicle replenishment reached 35-50% of wild-type levels. Abstract Number: 355. The loss of 40% of synaptic ribbons in these IHCs could not be prevented, indicating a role of otoferlin in early synapse maturation. ET. To date, however, otoferlin has been studied almost exclusively in mouse models, and no rescue experiments have been reported. Otoferlin Deficiency In Zebrafish Results In Defects In Balance And Hearing: ... Otoferlin, a six-C2 domain transmembrane protein linked to deafness in humans, is hypothesized to play a role in exocytosis at hair cell ribbon synapses. Abstract number: 536 Title: Mechanisms of Promoter-Driven AAV Toxicity in the Ear The Otoferlin protein is large and is delivered to the inner ear using two standard gene therapy vectors (AAV) and … We conclude that otoferlin plays an evolutionarily conserved role in vertebrate hearing, and that truncated forms of otoferlin can rescue hearing and balance. Mutations in the otoferlin gene are linked to severe congenital hearing loss, a common type of deafness in which patients can hear almost nothing. Otoferlin Deficiency in Zebrafish Results in Defects in Balance and Hearing: Rescue of the Balance and Hearing Phenotype with Full-Length and Truncated Forms of Mouse Otoferlin • Genetically driven otoferlin deficiency causes congenital severeprofound hearing loss • Tightly controlled expression of otoferlin in the sensory hair cells with cell-selective promoter provided robust and durable hearing rescue in preclinical studies Additional NHP data for the gene therapy program targeting otoferlin deficiency - H2 2020 Confirmatory preclinical PoC studies for the program targeting Usher syndrome type 1 - … To browse Academia.edu and the wider internet faster and more securely, please take a few seconds to upgrade your browser. Otoferlin functions in hair-cell exocytosis. The company is uniquely placed, through its platforms and pipeline of potential therapeutics, to make a lasting positive impact on hundreds of thousands of … Rank. 2015 Jan 12. pii: MCB.01439-14. "Beyond DB-OTO, we remain encouraged by the progress in our gene therapy programs for … Ph. Sensory hair cells convert mechanical motion into chemical signals. Research suggests otoferlin, which is in the cochlea of the inner ear, acts as a calcium-sensitive linker protein and that a mutation in it weakens the binding between the protein and a calcium synapse in the ear; deficiencies in that interaction are a likely cause of otoferlin-related hearing … Here we review progress toward understanding otoferlin, a multi-C2 domain protein identified a decade ago by genetic analysis of human deafness. C2… Otoferlin homologous proteins in humans that have been shown to be associated with human diseases are dysferlin and myoferlin. Videos involving Gene Tools products on JoVE, Download Protocols, Publications and Useful Documents. Otoferlin deficiency in zebrafish results in defects in balance and hearing: rescue of the balance and hearing phenotype with full-length and truncated forms of mouse otoferlin. Otoferlin occurs in multiple splice variants, including a 1,997–amino acid form, consisting of a transmembrane segment and six cytoplasmic C2 domains, and a shorter three–C2 domain isoform found in humans but not mice ( Yasunaga et al., 2000 ). The short form of the encoded protein has three C2 domains, a single carboxy-terminal transmembrane domain found also in the C. elegans spermatogenesis factor FER-1 and human dysferlin, while the long form has six C2 domains. Otoferlin deficiency in zebrafish results in defects in balance and hearing: rescue of the balance and hearing phenotype with full-length and truncated forms of mouse otoferlin. Authors: Chatterjee P, Padmanarayana M, Abdullah N, Holman CL, LaDu J, Tanguay RL, Johnson CP. Last day 1 week 1 month all. Otoferlin plays a critical role in exocytosis of synaptic vesicles at the inner hair cell synapse, and mutations in OTOF, the gene encoding otoferlin, are associated with autosomal … • Genetically driven otoferlin deficiency causes congenital severeprofound hearing loss • Tightly controlled expression of otoferlin in the sensory hair cells with cell-selective promoter provided robust and durable hearing rescue in preclinical studies • We are advancing DB-OTO to the clinic for patients with congenital hearing loss due to biallelic OTOF mutations . LiveRank. Remarkably, truncated forms of otoferlin retaining the C-terminal C2F domain also rescued the otoferlin knockdown phenotype, while the individual N-terminal C2A domain did not. otoferlin; News tagged with otoferlin. Four novel mutations were identified: c.2122C>T (p.Arg708Ter), c.4275G>A (p.Trp1425Ter), c.4362+2T>G, and c.5860_5862delATC (p.Ile1954del). Otoferlin is a large multi–C2 domain protein proposed to act as a calcium sensor that regulates synaptic vesicle exocytosis in cochlear hair cells. Although mutations in otoferlin have been associated with deafness, its contribution to neurotransmitter release is unresolved. Cell. (PMID:25582200 PMCID:PMC4333087) Current research reveals requirements for otoferlin in priming and fusion of synaptic vesicles during sound encoding. Title: Development of an AAV-Based Gene Therapy for Children with Congenital Hearing Loss Due to Otoferlin Deficiency (DB-OTO) Summary: An overview of preclinical DB-OTO data from mice and non-human primates Date and time: Tuesday May 11, 2021, 8:00 a.m. – 10:00 a.m. In the cochlea, otoferlin was selectively expressed in auditory hair cells. Mol. In addition to these data, Decibel presented preclinical findings demonstrating that DB-OTO restored normal hearing sensitivity in animal models of otoferlin deficiency. This EPSC heterogeneity led to the hypothesis of synchronized multiquantal release (MQR) at hair cell synapses (Glowatzki and Fuchs, 2002; Keen an… Key information Otoferlin defiency is responsible for up to 8% of all congenital hearing loss Prevalence: around 20 000 patients in the USA and EU Incidence: around … Philomath, OR 97370 USA You can download the paper by clicking the button above. Several presentations will focus on DB-OTO, Decibel’s investigational gene therapy being developed to restore hearing in children with a deficiency in the otoferlin gene, and DB-ATO, a regenerative gene therapy program designed to restore balance in patients with bilateral vestibulopathy, or BVP, by regenerating lost hair cells within the vestibule. Therefore, otoferlin seems incapable of functionally replacing Syt1 in chromaffin cell exocytosis. In early 2021, we announced encouraging preclinical results on our lead gene therapy program, DB-OTO, for the treatment of people with otoferlin deficiency. Citation: Mol Cell Biol. Harmonin (Ush1c) is required in zebrafish Müller glial cells for photoreceptor synaptic development and function, Knockdown of monocarboxylate transporter 8 ( mct8 ) disturbs brain development and locomotion in zebrafish, Duplicated genes with split functions: independent roles of protocadherin15 orthologues in zebrafish hearing and vision, Zebrafishpax5 regulates development of the utricular macula and vestibular function, Amigo adhesion protein regulates development of neural circuits in zebrafish brain. Last day 1 week 1 month all. Acoustic clicks evoked auditory brainstem responses …
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