Astra Dinculescu

Astra Dinculescu, PhD

Assistant Professor

Department: MD-OPHTHALMOLOGY
Business Phone: (352) 273-7548
Business Email: astra@ufl.edu

About Astra Dinculescu

Dr. Dinculescu received her Ph.D. in Biochemistry from University of Florida in 2002. She completed her postdoctoral training in the laboratory of Dr. William Hauswirth, one of the pioneers of retinal gene therapy using adeno-associated viral vectors (AAVs). She developed an interest in age-related eye diseases following her discovery that mutant S163R C1QTNF5, associated with late-onset retinal degeneration (L-ORD), generates widespread, prominent deposits, reminiscent of those present in patients (Dinculescu et al., Invest Ophthalmol Vis Sci. 2015). She tested novel capsid-mutant AAV vectors in the retina, uncovered their ability to penetrate retinal layers, and systematically characterized their unique transduction patterns, paving the way for future studies essential for ocular gene-therapy to prevent blindness in retinal degenerative diseases (Petrs-Silva et al., Mol Ther. 2011).

In 2016, she was recognized as an Emerging Vision Scientist by the National Alliance for Eye and Vision Research. In the same year, she established an independently funded research program, primarily focused on developing a treatment to prevent blindness in Usher syndrome type III (USH3), an inherited disorder caused by mutations in the Clarin-1 (CLRN1) gene. In her recent studies, Dr. Dinculescu provided evidence that CLRN1 transcripts display a similar pattern of expression in several distinct species, including humans, concentrating in the inner nuclear layer, specifically in Müller glia (Xu et al., J Pathol. 2020; Dinculescu et al., Int Ophthalmol Clin. 2021). This discovery opens new directions towards future mechanistic and therapeutic studies to prevent vision loss in USH3 patients.

Teaching Profile

Courses Taught
2020-2022
GMS6009 Principles of Drug Action and Therapeutics
2017-2020
GMS6791 Visual Neuroscience Journal Club
2021
GMS6070 Sensory and Motor Systems
2022
GMS6252 Molecular Therapy II ? Disease Targets and Applications

Research Profile

USH syndrome represents the most common genetic cause of combined deafness and blindness, with an estimated prevalence ranging from 4 to 17 cases per 100,000 people worldwide. It results in the progressive loss of the retinal photoreceptors in the eye and the auditory hair cells in the inner ear. Research conducted in our laboratory is mainly dedicated to developing therapeutic strategies for Usher syndrome type III (USH3), a disorder caused by mutations in the CLRN1 gene, leading to progressive hearing loss and retinal degeneration. The biological function of CLRN1 in the retina is currently not understood. Importantly, there are no therapeutic approaches that prevent the loss of light-sensitive photoreceptor neurons in USH3 patients. A major challenge hindering the development of treatments to prevent blindness in this disorder is the lack of models that mimic the human vision loss. For this reason, we are developing new models that will contribute greatly to the advancement of our understanding of this disorder, as well as our ability to treat it. Our goals are to understand the roles of CLRN1 protein in Müller glia and how its omission specifically impacts the postnatal and adult retina, in order to develop safe AAV-based gene-therapy tools for preventing blindness in USH3 patients.

Publications

2022
A Modified Arrestin1 Increases Lactate Production in the Retina and Slows Retinal Degeneration.
Human gene therapy. 33(13-14):695-707 [DOI] 10.1089/hum.2021.272. [PMID] 35081746.
2021
Retinal Gene Therapy for Usher Syndrome: Current Developments, Challenges, and Perspectives.
International ophthalmology clinics. 61(4):109-124 [DOI] 10.1097/IIO.0000000000000378. [PMID] 34584048.
2020
Clarin-1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome.
The Journal of pathology. 250(2):195-204 [DOI] 10.1002/path.5360. [PMID] 31625146.
2019
Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy.
Human gene therapy. 30(5):632-650 [DOI] 10.1089/hum.2018.192. [PMID] 30499344.
2019
Systemic Delivery of Genes to Retina Using Adeno-Associated Viruses.
Advances in experimental medicine and biology. 1185:109-112 [DOI] 10.1007/978-3-030-27378-1_18. [PMID] 31884597.
2018
Co-Expression of Wild-Type and Mutant S163R C1QTNF5 in Retinal Pigment Epithelium.
Advances in experimental medicine and biology. 1074:61-66 [DOI] 10.1007/978-3-319-75402-4_8. [PMID] 29721928.
2018
Cone Phosphodiesterase-6γ’ Subunit Augments Cone PDE6 Holoenzyme Assembly and Stability in a Mouse Model Lacking Both Rod and Cone PDE6 Catalytic Subunits.
Frontiers in molecular neuroscience. 11 [DOI] 10.3389/fnmol.2018.00233. [PMID] 30038560.
2017
Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa.
Frontiers in neuroscience. 11 [DOI] 10.3389/fnins.2017.00342. [PMID] 28676737.
2017
Modeling and Preventing Progressive Hearing Loss in Usher Syndrome III.
Scientific reports. 7(1) [DOI] 10.1038/s41598-017-13620-9. [PMID] 29044151.
2016
AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy.
PloS one. 11(2) [DOI] 10.1371/journal.pone.0148874. [PMID] 26881841.
2015
Pathological Effects of Mutant C1QTNF5 (S163R) Expression in Murine Retinal Pigment Epithelium.
Investigative ophthalmology & visual science. 56(11):6971-80 [DOI] 10.1167/iovs.15-17166. [PMID] 26513502.
2015
Stability and Safety of an AAV Vector for Treating RPGR-ORF15 X-Linked Retinitis Pigmentosa.
Human gene therapy. 26(9):593-602 [DOI] 10.1089/hum.2015.035. [PMID] 26076799.
2014
Gene therapy in the rd6 mouse model of retinal degeneration.
Advances in experimental medicine and biology. 801:711-8 [DOI] 10.1007/978-1-4614-3209-8_89. [PMID] 24664762.
2014
Tyrosine capsid-mutant AAV vectors for gene delivery to the canine retina from a subretinal or intravitreal approach.
Gene therapy. 21(1):96-105 [DOI] 10.1038/gt.2013.64. [PMID] 24225638.
2013
Cone phosphodiesterase-6α’ restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6β-deficient rd10 mouse.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(29):11745-53 [DOI] 10.1523/JNEUROSCI.1536-13.2013. [PMID] 23864662.
2013
Review: the history and role of naturally occurring mouse models with Pde6b mutations.
Molecular vision. 19:2579-89 [PMID] 24367157.
2013
Targeting Tumor Hla Expression To Increase the Immunogenicity of Cancer Cells
Human Gene Therapy. 24(12)
2012
AAV-mediated gene therapy in mouse models of recessive retinal degeneration.
Current molecular medicine. 12(3):316-30 [PMID] 22300136.
2012
Gene therapy for retinitis pigmentosa caused by MFRP mutations: human phenotype and preliminary proof of concept.
Human gene therapy. 23(4):367-76 [DOI] 10.1089/hum.2011.169. [PMID] 22142163.
2012
Tyrosine-mutant AAV8 delivery of human MERTK provides long-term retinal preservation in RCS rats.
Investigative ophthalmology & visual science. 53(4):1895-904 [DOI] 10.1167/iovs.11-8831. [PMID] 22408006.
2011
Alternative splice variants of the USH3A gene Clarin 1 (CLRN1).
European journal of human genetics : EJHG. 19(1):30-5 [DOI] 10.1038/ejhg.2010.140. [PMID] 20717163.
2011
Long-term retinal function and structure rescue using capsid mutant AAV8 vector in the rd10 mouse, a model of recessive retinitis pigmentosa.
Molecular therapy : the journal of the American Society of Gene Therapy. 19(2):234-42 [DOI] 10.1038/mt.2010.273. [PMID] 21139570.
2011
Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina.
Molecular therapy : the journal of the American Society of Gene Therapy. 19(2):293-301 [DOI] 10.1038/mt.2010.234. [PMID] 21045809.
2011
Quantifying transduction efficiencies of unmodified and tyrosine capsid mutant AAV vectors in vitro using two ocular cell lines.
Molecular vision. 17:1090-102 [PMID] 21552473.
2009
Clarin-1, encoded by the Usher Syndrome III causative gene, forms a membranous microdomain: possible role of clarin-1 in organizing the actin cytoskeleton.
The Journal of biological chemistry. 284(28):18980-93 [DOI] 10.1074/jbc.M109.003160. [PMID] 19423712.
2009
Dose-Dependent Humoral Immune Responses To Intravitreal Delivery of Aav Vectors and Strategies To Circumvent
Molecular Therapy. 17
2009
Functional interchangeability of rod and cone transducin alpha-subunits.
Proceedings of the National Academy of Sciences of the United States of America. 106(42):17681-6 [DOI] 10.1073/pnas.0901382106. [PMID] 19815523.
2009
High-efficiency transduction of the mouse retina by tyrosine-mutant AAV serotype vectors.
Molecular therapy : the journal of the American Society of Gene Therapy. 17(3):463-71 [DOI] 10.1038/mt.2008.269. [PMID] 19066593.
2008
AAV-mediated gene therapy for retinal degeneration in the rd10 mouse containing a recessive PDEbeta mutation.
Investigative ophthalmology & visual science. 49(10):4278-83 [DOI] 10.1167/iovs.07-1622. [PMID] 18586879.
2008
Downregulation of p22phox in retinal pigment epithelial cells inhibits choroidal neovascularization in mice.
Molecular therapy : the journal of the American Society of Gene Therapy. 16(10):1688-94 [DOI] 10.1038/mt.2008.164. [PMID] 18665154.
2008
Intraocular route of AAV2 vector administration defines humoral immune response and therapeutic potential.
Molecular vision. 14:1760-9 [PMID] 18836574.
2007
Anti-clarin-1 AAV-delivered ribozyme induced apoptosis in the mouse cochlea.
Hearing research. 230(1-2):9-16 [PMID] 17493778.
2006
Arrestin translocation in rod photoreceptors.
Advances in experimental medicine and biology. 572:455-64 [PMID] 17249609.
2006
Disease mechanisms and gene therapy in a mouse model for X-linked retinoschisis.
Advances in experimental medicine and biology. 572:283-9 [PMID] 17249585.
2005
Adeno-associated virus-mediated expression of vascular endothelial growth factor peptides inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy.
Human gene therapy. 16(11):1247-54 [PMID] 16259558.
2005
Adeno-associated virus-vectored gene therapy for retinal disease.
Human gene therapy. 16(6):649-63 [PMID] 15960597.
2005
Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis.
Molecular therapy : the journal of the American Society of Gene Therapy. 12(4):644-51 [PMID] 16027044.
2004
The surface of visual arrestin that binds to rhodopsin.
Molecular vision. 10:392-8 [PMID] 15215746.
2002
Insertional mutagenesis and immunochemical analysis of visual arrestin interaction with rhodopsin.
The Journal of biological chemistry. 277(14):11703-8 [PMID] 11809770.
1993
The effect of dihydronicotinate N-substitution on the brain-targeting efficacy of a zidovudine chemical delivery system.
Pharmaceutical research. 10(9):1356-62 [PMID] 8234177.

Grants

Sep 2022 ACTIVE
Generation and Characterization of Novel Large Animal Models of Usher Syndrome Type 3
Role: Principal Investigator
Funding: NATL INST OF HLTH NEI
Jun 2021 ACTIVE
Generation and Characterization of Swine Models of Usher Syndrome Type 3
Role: Principal Investigator
Funding: FOU FOR FIGHTING BLINDNESS
Sep 2019 ACTIVE
Transcriptional control of proteostasis in photoreceptors
Role: Co-Investigator
Funding: NATL INST OF HLTH NEI
Jul 2017 – Aug 2019
The role of basal C1QTNF5-S163R mutant deposits in drusen formation: implications for AMD
Role: Principal Investigator
Funding: BRIGHTFOCUS FOU
Sep 2016 – Aug 2022
CLARIN 1 RETINAL FUNCTION AND THERAPEUTIC IMPLICATIONS FOR USH3
Role: Principal Investigator
Funding: NATL INST OF HLTH NEI

Contact Details

Phones:
Business:
(352) 273-7548
Emails:
Business:
astra@ufl.edu
Addresses:
Business Mailing:
PO Box 100284
GAINESVILLE FL 32610
Business Street:
1600 SW ARCHER RD ARB R1-236
GAINESVILLE FL 326110001