Biology subjects

Westerfield, M.

Publications and source records attributed to Westerfield, M..

5 recordsLinked to original sources

bioRxiv2025

Mini-Pcdh15b Gene Therapy Rescues Visual Deficits in a Zebrafish Model of Usher Syndrome Type 1F

Usher syndrome type 1F (USH1F) is a severe inherited disorder caused by mutations in PCDH15, resulting in congenital deafness, vestibular dysfunction, and progressive retinal degeneration leading to blindness. While cochlear implantation can restore hearing, no therapeutic interventions currently exist for vision loss. Gene augmentation therapy represents a promising approach; however, the PCDH15 coding sequence ([~]5.3 kb) exceeds the packaging capacity of adeno-associated virus (AAV) vectors. To overcome this limitation, we previously engineered shortened "mini-PCDH15" constructs that retain key structural and functional domains while fitting within a single AAV. Among these, the mini-PCDH15-V4 variant successfully restored hearing in Pcdh15-deficient mice. Here, we investigated the ability of a cone-targeted mini-pcdh15b-V4 transgene to rescue vision in a zebrafish model of USH1F. Untreated pcdh15b-deficient zebrafish exhibited severe structural and functional defects of the retina, including disorganized and shortened photoreceptor outer segments, disrupted calyceal processes, and markedly reduced electroretinogram (ERG) and optokinetic response (OKR) performance. Targeted expression of mini-pcdh15b-V4 recapitulated typical localization of Pcdh15b to calyceal processes and outer segment membranes, rescued photoreceptor architecture, and re-established both structural organization and functional output. Treated mutants exhibited improved visual tracking behavior and full recovery of ERG a-wave and b-wave amplitudes, indicating restoration of photoreceptor and synaptic function. Importantly, mini-pcdh15b-V4 expression produced no adverse effects in wild-type or heterozygous fish, supporting the safety of cone-specific expression. Together, these findings demonstrate that mini-pcdh15b-V4 can restore both photoreceptor structure and visual function in pcdh15b-deficient zebrafish. This work establishes the pcdh15b mutant zebrafish as a powerful preclinical model for studying USH1F retinopathy and supports the translational potential of rationally engineered mini-PCDH15 constructs as a feasible gene therapy approach for preventing or reversing vision loss in individuals with USH1F.

neuroscience↗

bioRxiv2023

Hexafluoro slows retinal degeneration and improves visual function in zebrafish models of Usher syndrome 1F

Usher syndrome is the leading genetic cause of deafblindness, affecting hundreds of thousands of people worldwide. The deafness can be addressed with hearing aids or cochlear implants, but there is currently no treatment for the vision loss, which is due to progressive degeneration of retinal photoreceptors. Studies in animal models of Usher syndrome have shown that photoreceptor degeneration is exacerbated by exposure to bright light, and other studies have shown that light-induced photostress reduces mitochondrial function. We previously synthesized hexafluoro and showed that it is a potent Sirt3 activator that promotes mitochondrial respiration. Here we examined the efficacy of hexafluoro as a potential therapeutic for treatment of vison loss in a zebrafish model of Usher syndrome type 1F, which exhibits early and severe vision defects along with vestibular dysfunction as seen in Usher type 1 pathology. We find that hexafluoro improves visual function, reduces photoreceptor degeneration, and protects the retina against exposure to bright light in this USH1F model.

neuroscience↗

bioRxiv2022

From Multi-Allele Fish to Non-Standard Environments, How ZFIN Assigns Phenotypes, Human Disease Models, and Gene Expression Annotations to Genes

Danio rerio is a model organism used to investigate vertebrate development. Manipulation of the zebrafish genome and resultant gene products by mutation or targeted knockdown has made the zebrafish a good system for investigating gene function, providing a resource to investigate genetic contributors to phenotype and human disease. Phenotypic outcomes can be the result of gene mutation, targeted knockdown of gene products, manipulation of experimental conditions, or any combination thereof. Zebrafish have been used in various genetic and chemical screens to identify genetic and environmental contributors to phenotype and disease outcomes. The Zebrafish Information Network (ZFIN) is the central repository for genetic, genomic, and phenotypic data that result from research using Danio rerio. Here we describe how ZFIN annotates phenotype, expression, and disease model data across various experimental designs, how we computationally determine wild-type gene expression, the phenotypic gene, and how these results allow us to propagate gene expression, phenotype, and disease model data to the correct gene, or gene related entity.

bioinformatics↗

bioRxiv2021

Zebrafish Information Network, the knowledgebase for Danio rerio research

The Zebrafish Information Network (ZFIN, zfin.org) is the central repository for zebrafish genetic and genomic data. ZFIN expertly curates, integrates, and displays zebrafish data including genes, alleles, human disease models, gene expression, phenotype, gene function, orthology, morpholino, CRISPR, TALEN, and antibodies. ZFIN makes zebrafish research data Findable, Accessible, Interoperable, and Reusable (FAIR) through nomenclature, curatorial and annotation activities, web interfaces, and data downloads. ZFIN is a founding member of the Alliance of Genome Resources, providing zebrafish data for integration into the cross species platform as well as contributing to model organism data harmonization efforts.

genetics↗

bioRxiv2017

TOWARDS A GLOBAL SUPPORT OF CORE DATA RESOURCES FOR THE LIFE SCIENCES

On November 18-19, 2016, the Human Frontier Science Program Organization (HFSPO) hosted a meeting of senior managers of key data resources and leaders of several major funding organizations to discuss the challenges associated with sustaining biological and biomedical (i.e., life sciences) data resources and associated infrastructure. A strong consensus emerged from the group that core data resources for the life sciences should be supported through a coordinated international effort(s) that better ensure long-term sustainability and that appropriately align funding with scientific impact. Ideally, funding for such data resources should allow for access at no charge, as is presently the usual (and preferred) mechanism. Below, the rationale for this vision is described, and some important considerations for developing a new international funding model to support core data resources for the life sciences are presented.

scientific communication and education↗