Method of Enhancing Delivery of Therapeutic Compounds to the Eye

a technology of therapeutic compounds and eye, which is applied in the direction of algae medical ingredients, peptide/protein ingredients, drug compositions, etc., can solve the problems of limited delivery effect of current methods, such as intravitreal injection or implanted drug delivery devices, and achieve the effects of improving or restoring light sensitivity, improving or restoring vision

Inactive Publication Date: 2018-03-08
WAYNE STATE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about using a therapeutic agent to increase or restore light sensitivity in a subject. The therapeutic agent can be a small molecule, nucleic acid, antibody, or peptide. The nucleic acid can be a viral vector, plasmid, or siRNA, which encodes an opsin gene. The viral vector can be a recombinant AAV viral vector or rAAV. The therapeutic agent is administered to the vitreous of the eye. The invention can also improve or restore vision in a subject.

Problems solved by technology

Delivery of therapeutic compounds to specific ocular tissues affected by an ocular disease or disorder, such as the retina, is a challenge.
Current methods, such as intravitreal injection or implanted drug delivery devices, are still limited in the efficacy of delivery.
Specifically, the therapeutic agents are often localized only to the immediate areas surrounding the delivery site, and fail to permeate or diffuse beyond intervening ocular structures or throughout the targeted ocular tissue, thereby severely limiting the efficacy of such therapeutics.

Method used

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  • Method of Enhancing Delivery of Therapeutic Compounds to the Eye
  • Method of Enhancing Delivery of Therapeutic Compounds to the Eye
  • Method of Enhancing Delivery of Therapeutic Compounds to the Eye

Examples

Experimental program
Comparison scheme
Effect test

example 1

ncreases Delivery of AAV2-Vector Encoding Chop2 to the Retina

[0105]Delivery of a therapeutic viral construct encoding a functional GFP-channelopsin-2 protein to the retina was examined. Injection of 6×1012 vg / ml of AAV2 vector AAV2 / 2-ChR2-GFP-WPRE-hGHpA in control (FIG. 1A) or co-injection with plasmin (FIG. 1B) was performed into the vitreous space of the eye of one month old C56BL / 6J. The concentration of plasmin injected with vector was 0.025IU / eye. After one month, the mice retinas were isolated, and retinal vertical sections were prepared. The sections were immunostained and cells were counted. Immunofluorescence analysis of the sections showed that co-injection with plasmin increased the transduction efficiency of the therapeutic AAV2-ChR2-GFP vector, as evidenced by increased fluorescence in comparison to control (FIG. 1).

example 2

ncreases Transduction Efficiency in Retinal Ganglion Cells

[0106]Using the same experimental set-up as in Example 1, a vector (2×1012 vg / ml) encoding GFP was co-injected with either control or varying concentrations of plasmin: low (L=0.005 IU / eye), middle (M=0.025IU / eye), and high (H=0.100IU / eye). After 1 month, retinal whole mounts were prepared and immunostained. Representative images for each plasmin concentration and control are shown in FIG. 2. As shown, treatment with plasmin increases GFP expression.

[0107]To further quantify these results, GFP-expressing retinal ganglion cells were counted from multiple unit areas of 223 μm×167 μm. The results are presented in FIG. 3A. As shown, treatment with low, middle and high doses of plasmin resulted in statistically significantly increased levels of GFP expression in retinal ganglion cells.

[0108]Neurotoxicity as a result of plasmin injection was also examined. The retinal whole mounts were stained with DAPI for cell-counting. The numbe...

example 3

ncreases Transduction Efficiency in Retinal Bipolar Cells

[0109]Comparison of the transduction efficiency of a viral vector encoding mCherry fluorescent protein when co-injected with different concentrations of plasmin was assessed in vivo. Specifically, overall levels and the localization of mCherry expression throughout the retina were examined. An AAV2 vector with an Y444F capsid mutation carrying mCherry under control of an mGluR6 promoter were injected at a concentration of 2×1012 vg / ml. The mGluR6 promoter directs expression of mCherry specifically to the retinal bipolar cells.

[0110]The AAV2 mCherry vector was co-injected with three doses of plasmin, high (H=0.100IU / eye), middle (M=0.025IU / eye), and low (L=0.005IU / eye). After 1 month, the retinas were isolated and retinal whole-mounts were prepared. Transduction efficiency was evaluated by immunostaining of mCherry for immunofluorescence analysis and cell counting. Cells were counted from multiple unit areas of 223 μm×167 μm.

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Abstract

The invention provides methods for enhancing the delivery of therapeutic compounds to the eye of a subject by administering plasmin or derivatives thereof and the therapeutic compounds to the eye.

Description

RELATED APPLICATIONS[0001]This application is a continuation application of U.S. application Ser. No. 14 / 777,420 filed on Sep. 15, 2015, which is a 371 of International Application No. PCT / US2014 / 026224, filed Mar. 13, 2014, which claims priority to, and the benefit of, U.S. Provisional Application No. 61 / 785,015, filed on Mar. 14, 2013; the contents of each of which are hereby incorporated by reference in its entirety.GOVERNMENT SUPPORT[0002]This invention was made with government support under EY017130 awarded by the National Institutes of Health. The government has certain rights in the invention.INCORPORATION OF SEQUENCE LISTING[0003]The contents of the text file named “RTRO-704 / C01US_SeqList.txt,” which was created on Aug. 14, 2017 and is 25.7 KB in size, are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0004]This invention relates generally to methods of enhancing the delivery of therapeutic compounds to the eye.BACKGROUND OF THE INVENTION[0005]The ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K48/00A61K31/7088A61K31/713A61K36/05A61K38/16A61K38/36A61K38/48
CPCC12Y304/21007A61K48/0075A61K9/0048A61K31/7088A61K31/713A61K36/05A61K38/16A61K38/36A61K38/484A61K48/0008A61P27/00A61P27/02
Inventor PAN, ZHUO-HUAIVANOVA, ELENA
Owner WAYNE STATE UNIV
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