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Wolfgang Baehr, PhD
BASIC RESEARCH PROJECT
Department of Ophthalmology and Visual Sciences
University of Utah Health Science Center
Salt Lake City, UT
Dr. Baehr’s Research Project
Therapy for a Mouse Model of Joubert Syndrome
Current Research Interests
Dr. Baehr’s lab is interested in understanding mechanisms leading to retina disease and developing gene-based therapies for non-syndromic and syndromic ciliopathies, focusing mainly on the retina. In this proposal, he will focus exclusively on the gene encoding ARL13b, the function of which is directly related to ARL3. Null mutations in this gene are associated with Joubert Syndrome in human, but are embryonic lethal in mouse. Dr. Baehr will study the consequences of ARL13b deletion specifically in retina and in photoreceptors. The goal is to devise gene-based therapies to ameliorate or cure the retina disease.
Progress in 2016
Dr. Baehr has published three papers on NPHP5 and ARL3. 1) Dr. Baehr probed the function of Arf-like protein 3 (ARL3) by generating rod photoreceptor- and retina-specific Arl3 deletions. Arl3-/- rods and cones expressing Cre recombinase during embryonic development formed neither connecting cilia nor outer segments, and degenerated rapidly. Absence of cilia infers participation of ARL3 in ciliogenesis and axoneme formation. 2) Mutations in RPGR (retinitis pigmentosa GTPase regulator) are the most common cause of X-linked RP. Dr. Baehr showed that phenotypic expression of Rpgr-loss in mice is influenced genetically by the loss of Cep290, a human ciliopathy gene. 3) Null mutations in the human IQCB1/NPHP5 gene encoding nephrocystin-5 are the most frequent cause of Senior-Løken syndrome (SLS). Dr. Baehr established that nephrocystin-5 is essential for photoreceptor outer segment formation, but dispensable for kidney and MEF ciliary formation.
Plans for 2017
Aim 1) Generation of a retina-specific ARL13b knockout mice. These conditional knockout mouse lines will enable him to analyze ARL13b function at specified developmental times, taking advantage of generating knockout mice on the EGFP-CETN2 background. Methods of phenotyping knockout mice will consist of electroretinography, OptoMotry, optical coherence tomography (OCT), confocal and electron microscopy.
Aim 2) Developing gene therapy vectors to rescue retinal degeneration in Arl13b-/- mice. ARL13b-associated Joubert Syndrome mutations are loss-of-function mutations, therefore Dr. Baehr will develop a ‘gene replacement’ therapeutic strategy to cure the disease. The retinal degeneration in Arl13b knockout mice is expected to be fast, necessitating injections of virus in the first postnatal week. Expression of wild-type ARL13b in predegenerate photoreceptors on Nrl-/- is predicted to slow disease progression. Compared to untreated littermates, the AAV-treated mice may show normal photoreceptor OS trafficking and improved retinal morphology and function.
Progress in 2015
Dr. Baehr has generated an NPHP5 knockout mouse, a model for LCA without kidney disease (paper submitted), and is in the process of generating an NPHP10 knockout mouse to determine its phenotype. The goal is replicate human pathology in mouse and devise gene-based therapies to ameliorate or cure the retina disease. He has submitted a paper establishing that nephrocystin-5 is a novel LCA gene whose function is essential for photoreceptor ciliogenesis, but dispensable for kidney cilia formation. A second paper was submitted by a grad student who was paid in part by the RRF Award.