rAAV-guanylate cyclase compositions and methods for treating lebers congenital amaurosis-1 (LCA1)

Patent metadata

Field	Value
Publication number	US-9816108-B2
Application number	US-201113643074-A
Country	US
Kind code	B2
Filing date	Apr 22, 2011
Priority date	Apr 23, 2010
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

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).

First claim

What is claimed is:

1. A method for treating a human suffering from Leber congenital amaurosis-1 (LCA1), wherein the human has a defect, deficiency, or total absence of biologically-active retGC1 protein in at least one eye, as compared to the level of biologically-active retGC1 protein in an eye of a normal, untreated human, the method comprising: introducing into at least a first population of human photoreceptor cells an rAAV vector comprising at least a first polynucleotide that comprises a photoreceptor-specific human rhodopsin kinase promoter, operably linked to at least a first nucleic acid segment that encodes a first biologically-active, retinal-specific human guanylate cyclase polypeptide that comprises a first contiguous amino acid sequence region that is at least about 95% identical to a first sequence region of at least 80-contiguous-amino-acid sequence from SEQ ID NO:1, wherein the rAAV vector is contained within a AAV5 or AAV8 particle and wherein the rAAV vector is administered subretinally into at least a first site within one or both eyes of the human in an amount effective to produce a biologically-active human retGCI polypeptide in the one or more photoreceptor cells, such that production of the biologically-active human retGCI polypeptide in the one or more photoreceptor cells rescues and provides sustained restoration of photoreceptor function, thereby treating Leber congenital amaurosis-1 (LCA1).

2. The method of claim 1 , wherein the human is a neonate, a newborn, an infant, or a juvenile.

3. The method of claim 1 , wherein production of the biologically active retGCI polypeptide in the one or more photoreceptor cells a) preserves one or more cone photoreceptors, b) restores one or more cone-mediated functions, c) restores visual behavior in one or both eyes, or d) any combination thereof.

4. The method of claim 1 , wherein production of the biologically active retGCI polypeptide persists in the one or more photoreceptor cells for a period of at least about three months following a single administration of the rAAV vector into the first population of human photoreceptor cells within the one or both eyes of the human.

5. The method of claim 4 , wherein production of the biologically active retGCI polypeptide persists in the one or more-photoreceptor cells for a period of at least about six months following a single administration of the rAAV vector into the first population of human photoreceptor cells within the one or both eyes of the human.

6. The method of claim 5 , wherein production of the biologically active retGCI polypeptide persists in the one or more photoreceptor cells for a period of at least about ten months following a single administration of the rAAV vector into the first population of human-photoreceptor cells within the one or both eyes of the human.

7. The method of claim 1 , wherein the rAAV vector is contained within a AAV5 particle.

Assignees

• Boye Shannon Elizabeth
• Hauswirth William W
• Boye Sanford Leon
• Univ Florida

Inventors

• Boye Shannon Elizabeth
• Hauswirth William W
• Boye Sanford Leon

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• C12N2830/85

  mammalian · CPC title

• C12N2830/008

  cell type or tissue specific enhancer/promoter combination · CPC title

• C12N9/88 Primary

  Lyases (4.) · CPC title