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Raav-guanylate cyclase compositions and methods for treating leber's congenital amaurosis-1 (LCA1)

a technology of guanylate cyclase and amaurosis, which is applied in the field of molecular biology and virology, can solve the problems of impaired vision, slow pupil response, and retinal dysfunction, and achieve the effects of restoring the function of the cone, and increasing the level of biologically active retgc1 protein

Inactive Publication Date: 2018-04-12
UNIV OF FLORIDA RES FOUNDATION INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention is about introducing a gene called guanylate cyclase into cells to restore function to cone photoreceptors and restore vision in mammals. The gene is delivered using a virus called rAAV. The invention also includes the use of post-transcriptional elements to enhance the expression, stability, and translation of the gene. Overall, the invention provides a way to treat genetic blindness and restore vision.

Problems solved by technology

Symptoms of the disease include retinal dysfunction, wobbly eye movement (nystagmus), impaired vision, slow pupil response, and ultimately, blindness.
Presently there are no effective prophylactics or therapeutics available to prevent or treat LCA1 in humans.

Method used

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  • Raav-guanylate cyclase compositions and methods for treating leber's congenital amaurosis-1 (LCA1)
  • Raav-guanylate cyclase compositions and methods for treating leber's congenital amaurosis-1 (LCA1)
  • Raav-guanylate cyclase compositions and methods for treating leber's congenital amaurosis-1 (LCA1)

Examples

Experimental program
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Effect test

example 1

ted Gene Therapy Restores Visual Function and Behavior to a Mouse Model of LCA1

[0182]In this example, the inventors evaluated whether delivery of a species-specific version of retGC1 (i.e., murine) to cone cells of the postnatal GC1KO mouse could restore function to these cells. Serotype 5 AAV vectors were used to deliver mGC1 to photoreceptors of postnatal day 14 (P14) GC1KO mice. Electroretinogram (ERG) and behavioral testing were used to assess visual function and immunocytochemistry was used to examine therapeutic transgene expression, cone arrestin localization and cone photoreceptor densities in treated and untreated eyes.

[0183]This example demonstrates that an AAV vector subretinally delivered to one eye of P14 GC1 KO mice facilitated expression of wild type retGC1, restoration of visual function and behavior, and preservation of cone photoreceptors. Four weeks following injection, visual function (ERG) was analyzed in treated and untreated eyes. ERG was performed every two w...

example 2

del Containing a GC1 / GC2 Double Knockout

[0219]It is important to note that while only cone photoreceptors are affected in the GC1KO mouse (rods only lose partial function and they do not degenerate), LCA1 patients exhibit rod function loss and rod degeneration. The reason for this difference is speculated to be a species-specific difference in the dependence on GC2, a close relative of GC1 that is expressed in rod photoreceptors. Mouse rods are able to function in the absence of GC1 presumably because GC2 is capable of reconstituting activity; however in humans this is not the case. GC1 is required for rod function, hence the rod degeneration. A GC1 / GC2 double knockout mouse model was generated and shown to have rod function loss (in addition to cone function loss as seen in the GC1 K / O) (Baehr et al., 2007). It was proven through biochemical studies with this model that GC2 is what provides rod function in the absence of GC1. Having said that, it is the GC1 / GC2 double knockout mous...

example 3

d’ Murine Animal Model of LCA1

[0220]This example describes the creation of a “humanized” murine animal model of LCA1. In one embodiment, the mouse model contains a GC1 / GC2 / GCAP1 knockout. GCAP1 is the protein that activates GC1. To create an in-vivo system in which human GC1 expressed from a clinical grade rAAV vector designed for use in humans can be evaluated for function, a GC1 / GC2 / GCAP1 triple knockout hGCAP1 transgenic mouse is utilized. In this mouse, visual function is resorted by rAAV-mediated hGC1 interacting with hGCAP1 only (i.e., no endogenous murine GCAP1 is present). From this study, it is possible to determine whether the human GCAP1 protein is required to stimulate human GC1 activity in the mouse model, and whether function can be restored to cones and rods when the two human polypeptides are reconstituted and expressed in the non-human (i.e., murine) model of the disease. To generate the GC1 / GC2 / GCAP1 triple knockout hGCAP1 transgenic mouse the GC1 / GC2 double knocko...

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Abstract

Disclosed are viral vector compositions comprising polynucleotide sequences that express one or more biologically-active mammalian guanylate cyclase proteins. Also disclosed are methods for their use in preventing, treating, and / or ameliorating at least one or more symptoms of a disease, disorder, abnormal condition, or dysfunction resulting at least in part from a guanylate cyclase deficiency in vivo. In particular embodiments, the use of recombinant adeno-associated viral (rAAV) vectors to treat or ameliorate symptoms of Leber's congenital amaurosis, as well as other conditions caused by an absence or reduction in the expression of a functional retinal-specific guanylate cyclase 1 (retGC1).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application is a continuation of U.S. application Ser. No. 13 / 643,074, entitled “rAAV-GUANYLATE CYCLASE COMPOSITIONS AND METHODS FOR TREATING LEBER'S CONGENITAL AMAUROSIS-1 (LCA1)” filed on Oct. 23, 2012, which is a national stage filing under 35 U.S.C. § 371 of International Application No. PCT / US2011 / 033669, filed Apr. 22, 2011, which claims priority to U.S. Provisional Patent Application No. 61 / 327,521, filed Apr. 23, 2010, the entire contents of each of which are specifically incorporated herein in their entirety by express reference thereto.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under Grant Nos. EY011123 and EY008571 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention.NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT[0003]Not Applicable.BACKGROUND OF THE INVENTIONField of the Invention[0004]The...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N15/861A61K48/00C12N9/88C12N15/86A61K38/00
CPCC12N15/861A61K48/005C12N9/88C12N15/86C12N2750/14143A61K38/00C12N2830/008C12N2830/85C12Y406/01002A61K38/51C12N7/00C12N2750/14132A61P27/02A61P43/00C12N9/00C12N15/00C12N15/52C12N15/864
Inventor BOYE, SHANNON E.HAUSWIRTH, WILLIAM W.BOYE, SANFORD L.
Owner UNIV OF FLORIDA RES FOUNDATION INC
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