Formulations comprising antisense nucleotides to connexins

a technology of antisense nucleotides and connexins, which is applied in the field of forms, can solve the problems of general downregulation effect and difficulty which must be overcome, and achieve the effects of reducing neuronal loss, reducing neuronal cell death, and downregulating expression

Inactive Publication Date: 2007-02-15
OCUNEXUS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025] In still a further aspect, the invention provides a method of reducing neuronal cell death which would otherwise result from a neuronal insult to a specific site in the brain, spinal cord or optic nerve of a patient which comprises the step of administering a formulation as defined above to said site to downregulate expression of connexin protein(s) at and immediately adjacent said site.
[0026] Preferably, the formulation is administered to reduce neuronal loss due to physical trauma to the brain, spinal cord or optic nerve.
[0033] In yet a further aspect, the invention provides a method of decreasing scar formation in a patient who has suffered a wound which comprises the step of administering a formulation as defined above to said wound to downregulate expression of connexin protein(s) at and immediately adjacent the site of said wound.

Problems solved by technology

However, as a number of connexin proteins are expressed widely throughout the body, a general downregulatory effect is undesirable in inducing a therapeutic effect at a specific site.
However, there remain difficulties which need to be overcome.

Method used

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  • Formulations comprising antisense nucleotides to connexins
  • Formulations comprising antisense nucleotides to connexins
  • Formulations comprising antisense nucleotides to connexins

Examples

Experimental program
Comparison scheme
Effect test

experiment 2

[0100] Introduction

[0101] Astrocytes constitute the most abundant cell type in the mammalian brain. They are extensively coupled to one another and to neurons through gap junctions composed predominantly of connexin 43 (Giaume and McCarthy (1996)). Following ischaemia induced or physical brain damage these channels remain open and a spreading wave of depression (initiated by raised interstitial potassium and glutamate and apoptotic signals) is propagated (Cotrina et al., (1998); Lin et al (1998)). Waves of increased cytosolic calcium and second messenger molecules such as IP3 are slowly spread via the gap junction channels to neurons beyond the core of the damaged region, resulting in lesion spread in the 24-48 hours following the insult. In this manner, undamaged neighbouring cells are destroyed (Lin et al., 1998), the socalled bystander effect.

[0102] This experiment investigates the ability of the formulations of the invention to prevent this bystander effect.

Materials

[0103] ...

experiment 3

[0121] Introduction

[0122] The bystander effect in neural tissues whereby damaged neurons release toxins which spread and kill neighbouring cells is well documented. Experiment 2 shows that this effect can be reduced in the brain using an antisense oligodeoxynucleotide sustained release approach to knockdown the gap junction protein connexin 43.

[0123] Another tissue of similar composition to the brain is the spinal cord in which the neural population is supported by populations of glial cells, including astrocytes which are responsible for the neuroprotective effect by removing glutamate and excess calcium from the neural environment. This experiment investigates the ability of the formulations of the invention to reduce the spread of spinal cord lesions.

Materials

[0124] Oligodeoxynucleotides were prepared with the following sequences:

GTA ATT GCG GCA GGA GGA ATT GTT TCT(SEQ ID NO: 2)GTC (connexin 43)GAC AGA AAC AAT TCC TCC TGC CGC AAT(SEQ ID NO: 7)TAC (sense control)

[0125] Meth...

experiment 4

[0131] Introduction

[0132] To repair skin wounds a number of cell types, such as fibroblasts, endothelial cells and keratinocytes are activated to proliferate, migrate and lay down extracellular matrix to fill the wound.

[0133] Communication and intercellular signalling is a key feature of the wound healing process. Extracellular signalling mechanisms are thought to be the key players though it is also probable that intercellular signalling through the extensive networks of gap junction channels in the skin layers may also have a role. Calcium waves spreading away from injured cells through the epidermis may signal their damage. In normal wound healing connexin levels start to fall within 6 hours and take up to 6 days to recover. The roles that these changes play are not understood but one theory is that cells are released from their neighbours to divide rapidly, and then junctions reform to coordinate migration into and over the wound site.

[0134] This experiment investigates the a...

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Abstract

A therapeutic and / or cosmetic formulation comprising at least one anti-sense polynucleotide to a connexin protein together with a pharmaceutically acceptable carrier or vehicle is useful in site specific down regulation of connexin protein expression, particularly in reduction of neuronal cells death, wound healing, reduction of inflammation, decrease of scar formation and skin rejuvenation and thickening.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation of U.S. application Ser. No. 09 / 890,363, filed Jul. 27, 2001 (now issued as U.S. Pat. No. 7,098,190), which is a U.S. National Stage Application of International PCT Application No. PCT / GB00 / 00238, filed Jan. 27, 2000 (published as WO00 / 44409 on Aug. 3, 2000) and claims the benefit of priority to NZ 333928 (filed Jan. 27, 1999) and NZ 500190 (filed Oct. 7, 1999). The contents of each of which are hereby incorporated in their entireties.FIELD [0002] This invention relates to formulations for use in therapeutic and / or cosmetic treatments, particularly those in which a localised disruption in direct cell-cell communication is desirable. BACKGROUND [0003] Gap junctions are cell membrane structures which facilitate direct cell-cell communication. A gap junction channel is formed of two hemichannels (connexons), each composed of six connexin subunits. These connexins are a family of proteins, commonly named ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00A61K9/06C12N15/09A61K9/10A61K31/70A61K31/711A61K38/00A61K47/16A61K47/34A61K47/46A61P17/02A61P17/12A61P17/16A61P25/00A61P29/00A61P43/00C12N15/11C12N15/113
CPCA61K38/00C12N15/111C12N2320/32C12N2310/11C12N15/1138A61K31/711C07H21/04A61P17/00A61P17/02A61P17/12A61P17/16A61P25/00A61P29/00A61P43/00
Inventor BECKER, DAVID LAURENCEGREEN, COLIN RICHARD
Owner OCUNEXUS THERAPEUTICS INC
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