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Treatment of AMD using aav sflt-1

a technology of amd and sflt, which is applied in the field of treatment of amd using aav sflt1, can solve the problems of severe visual impairment, cumulative risk increase, retinal neovascularization and vision loss,

Inactive Publication Date: 2013-12-05
AVALANCHE AUSTRALIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent provides methods for treating CNV, particularly in the form of wet AMD, by administering a pharmaceutical composition containing a recombinant virus that expresses a soluble Fms-related tyrosine kinase-1 (sFLT-1) protein. The pharmaceutical composition can also include a VEGF inhibitor, such as an anti-VEGF antibody or a soluble receptor, to further enhance the treatment effect. The methods involve administering the pharmaceutical composition to the human subject through subretinal injection. The patent also provides methods for preventing CNV by administering a recombinant virus that expresses sFLT-1. The methods can be used for treating or preventing wet AMD.

Problems solved by technology

The wet form of AMD may develop rapidly and often results in blindness.
The pathological changes of the disease may cause severe visual impairment.
Intravitreal routes of administration may increase risks for serious complications such as infectious endophthalmitis and retinal detachment, for which cumulative risk increases with repeated administrations.
These diseases lead to retinal neovascularization and vision loss.

Method used

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  • Treatment of AMD using aav sflt-1

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0360]rAAV.sFlt-1

[0361]One example recombinant virus is rAAV.sFlt-1. It encodes a vector and a human form of the truncated, soluble VEGF receptor 1 (sFLT-1). The vector is a recombinant, replicative-deficient adeno-associated viral (rAAV) vector, of serotype 2.

[0362]The rAAV.sFlt-1 was manufactured under Good Manufacturing Practices (cGMP). At the manufacture site, the final product was aliquoted into sterile, low-virus-binding microcentrifuge tubes (individually wrapped, low-retention, sterilised flat cap vials) according to the protocol requirements (i.e. 200 μl of 1×1010 or 1×1011 viral genomes) and stored at −80° C. to await final product release. Each vial contained enough vector for use in a single patient (100 μl to be administered).

[0363]The recombinant virus, rAAV.sFlt-1, is a recombinant adeno-associated virus 2 (rAAV2) vector carrying the soluble VEGFR receptor 1 (VEGFR1) or sFLT-1 driven by the human cytomegalovirus (CMV) promoter. The rAAV.sFlt-1 vector and intact AAV2 ...

example 2

In Vitro Inhibition of VEGF-Induced Endothelial Cell Proliferation

[0370]Studies were performed to assess VEGF-induction of human umbilical vein endothelial cell (HUVEC) proliferation and to determine whether VEGF-induced HUVEC proliferation would be inhibited by rAAV-mediated sFLT-1. The presence of sFLT-1 in transduced cells was first confirmed by Western blot analysis of conditioned media (FIG. 2, panel a). Conditioned medium from rAAV.sFlt-1-transduced and rAAV.gfp-transduced 293 cells were added to VEGF-treated HUVECs in increasing dilutions. A control starvation medium (normal HUVEC growth medium without bovine endothelial growth factor) only was also included. Heparin was added to each well at 100 μg / mL. The relative VEGF-induced proliferation of HUVECS treated with VEGF and the different conditioned media was assayed by addition 25 μL of 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrozolium bromide (MTT, 5 mg / mL, Sigma) to each well for 4 hours at 37° C. The secreted sFLT-1 enc...

example 3

[0374]rAAV.sFlt-1 Studies in Mice

[0375]Transgenic mice (trVEGF029) with slow, but stable retinal neovascularization induced by transgenic expression of human VEGF from photoreceptor cells were used as a model for retinal neovascularization. Two separate studies with these mice have been conducted.

[0376]In the first mouse study, 13 transgenic mice were assessed for ocular neovascular changes before and after administration of the rAAV.sFlt-1 vector (1×1011 vector particles) in one eye and control vector in the contralateral eye. Eyes were assessed for neovascular changes using fluorescein angiography at one, three and eight months after injection. The extent, intensity and stage of neovascularization were graded (0-4) by three observers, masked to the treatment received in the eyes examined. There was a statistically significant overall reduction in the neovascular grading from a median grade of ‘3’ (before injection) to a median grade of ‘1’ at one month after injection (P=0.012). T...

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Abstract

The present disclosure provides compositions and methods for the prevention or treatment of ocular neovascularization, such as AMD, in a human subject, by administering subretinally a pharmaceutical composition comprising a pharmaceutically effective amount of a vector comprising a nucleic acid encoding soluble Fms-related tyrosine kinase-1 (sFlt-1) protein to the human subject.

Description

[0001]This application claims priority under 35 USC §119(e) to U.S. Provisional Application No. 61 / 647,461, filed May 15, 2012, U.S. Provisional Application No. 61 / 670,535, filed Jul. 11, 2012, U.S. Provisional Application No. 61 / 678,555, filed Aug. 1, 2012, U.S. Provisional Application No. 61 / 775,440, filed Mar. 8, 2013, each of which are incorporated by reference in their entirety.SEQUENCE LISTING[0002]This application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 14, 2013, is named 43016-702.201_SEtxt and is 86,152 bytes in size.BACKGROUND OF THE DISCLOSURE[0003]Age-related macular degeneration (AMD) is one of the leading causes of vision irreversible damage in people over the age of 50 years. AMD is clinically divided into two types as “dry” and “wet”. The wet form of AMD may develop rapidly and often results in blindness. The pathological changes of the d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00A61K45/06A61K35/76A61K39/00
CPCA61K48/00A61K35/761A61K45/06A61K31/7088A61K38/179A61K9/0048C07K14/71C07K2319/32C12Y207/10001C12Y207/10002C07K16/081C07K16/22A61K2039/505C07K2317/24C07K2317/55C07K2317/73A61K48/0075C12N15/86C12N2710/14044C12N2750/14143C12N2750/14141C12N2750/14171A61K38/45C12N9/12C12Y207/10A61P27/02A61P27/10A61P43/00A61P9/00A61P9/10A61P9/14A61P3/10A61K2300/00A61K39/395A61K49/0004C12N2750/14142A61B3/032C12N7/00
Inventor CONSTABLE, IAN J.RAKOCZY, ELIZABETH P.LAI, CHOOI-MAYCHALBERG, JR., THOMAS W.
Owner AVALANCHE AUSTRALIA
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