1. Preclinical studies for a retinoschisis clinical trial: We are currently evaluating the immune response to vector after intravitreal injection and are in the process of refining a transient immune suppression protocol. The vector design is be optimized for efficiency. 2. Retinitis Pigmentosa due to RPGR mutation: Animal models and vectors are being constructed and evaluated. 3. CEP290: Vectors have been prepared for this project and are being tested in vivo for expression and efficacy. This project has been expanded to examine several strategies for vector construction. The problem is that the CEP290 gene is 7.4 kb in length and AAV vectors can only package about 5 kb. A claim that AAV type 5 vectors could package intact vector genomes in the 8-9kb range was tested and was not supported by the data. A manuscript describing our results was published this year. We are now evaluating lentiviral vectors and compacted DNA particles as potential alternative gene transfer vehicles. 4. Improved therapeutics for neovascular diseases: In collaboration with Dr. Carmen Clapp of the Universidad Nacional Autonoma de Mexico, Juriquilla campus, we are examining a novel anti-angiogenic fragment of prolactin, called vasoinhibin, in the context of AAV vectors. AAV vectors encoding vasoinhibin, prolactin, and sFlt-1 (a soluble VEGF receptor fragment that acts as a competitive inhibitor) have been produced and have been tested in an animal model of diabetic retinopathy. These studies have been successful and a manuscript is being prepared. A new project examining the role that PDGF-C plays in the neovascular response has been initiated with Dr. Xuri Li of the National Eye Institute. Vectors have been made and we are waiting for the results of animal studies. 5. Vectors with transcytosis activity and low preexisting immunity in humans: This work is on-going.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Yu, Wenhan; Wu, Zhijian (2018) In Vivo Applications of CRISPR-Based Genome Editing in the Retina. Front Cell Dev Biol 6:53
Cukras, Catherine; Wiley, Henry E; Jeffrey, Brett G et al. (2018) Retinal AAV8-RS1 Gene Therapy for X-Linked Retinoschisis: Initial Findings from a Phase I/IIa Trial by Intravitreal Delivery. Mol Ther 26:2282-2294
Ye, Lei; Kan, Fangming; Yan, Tao et al. (2018) Author Correction: Enhanced antiviral and antifibrotic effects of short hairpin RNAs targeting HBV and TGF-? in HBV-persistent mice. Sci Rep 8:4247
Zhu, Wan; Shen, Fanxia; Mao, Lei et al. (2017) Soluble FLT1 Gene Therapy Alleviates Brain Arteriovenous Malformation Severity. Stroke 48:1420-1423
Yu, Wenhan; Mookherjee, Suddhasil; Chaitankar, Vijender et al. (2017) Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat Commun 8:14716
Sajgo, Szilard; Ghinia, Miruna Georgiana; Brooks, Matthew et al. (2017) Molecular codes for cell type specification in Brn3 retinal ganglion cells. Proc Natl Acad Sci U S A 114:E3974-E3983
Somasundaram, Preethi; Wyrick, Glenn R; Fernandez, Diego Carlos et al. (2017) C-terminal phosphorylation regulates the kinetics of a subset of melanopsin-mediated behaviors in mice. Proc Natl Acad Sci U S A 114:2741-2746
Ye, Lei; Kan, Fangming; Yan, Tao et al. (2017) Enhanced antiviral and antifibrotic effects of short hairpin RNAs targeting HBV and TGF-? in HBV-persistent mice. Sci Rep 7:3860
Hanke-Gogokhia, Christin; Wu, Zhijian; Sharif, Ali et al. (2017) The guanine nucleotide exchange factor Arf-like protein 13b is essential for assembly of the mouse photoreceptor transition zone and outer segment. J Biol Chem 292:21442-21456
Marangoni, Dario; Bush, Ronald A; Zeng, Yong et al. (2016) Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice. Mol Ther Methods Clin Dev 5:16011

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