WO2004082705A1

WO2004082705A1 - Treatment of dupuytren’s contracture

Info

Publication number: WO2004082705A1
Application number: PCT/GB2004/001192
Authority: WO
Inventors: William Bains
Original assignee: Delta Ltd
Priority date: 2003-03-18
Filing date: 2004-03-18
Publication date: 2004-09-30
Also published as: GB0306165D0

Abstract

Agents which reverse the wound-repair related proliferation of contractile cells in vascular disease may be used in the treatment of Dupuytren's Contracture or Disease. Suitable agents include those of the vascular endothelial growth factor family (VEGF).

Description

TREATMENT OF DUPUYTREN'S CONTRACTURE

Field of the Invention

This invention relates to the treatment of fibrotic diseases. Background to the Invention Dupuytren's Contracture is a progressive proliferative fibroplasia of the subcutaneous palmar tissue, which results in contraction of the finger joints which, ultimately, can become disabling (Calandruccio, J.H. (1998) Campbell's Operative Orthopaedic, 9th edn., ed S. Terry Canale Mosby (St. Louis, USA)). Patients suffer progressive development of thickened bands and nodules around the tendons of the palm and fingers - and sometimes the wrist - that leads to reduction in movement of the fingers and ultimately inability to extend them. Dupuytren's Disease is the term often given to non-disabling palmar fibroses: as progression can be slow, Dupuytren's Disease is substantially more common than Dupuytren's Contracture, but the aetiology of the two is believed to be the same.

The only demonstrated effective therapy is surgery to remove the bands and nodules, although radiotherapy is becoming accepted as effective in blocking disease progression (Seegenschmeidt, M.H., Olschewski, T., Guntrum, F. (2001) Int. J. Radiation Oncology, Biology, Phys. 49: 785-798). Both are effective in the short-term, but recurrence of the disease is almost inevitable. The mechanism by which the fibrosis is triggered or developed is unknown, although damage to and occlusion of the palmar microvasculature is likely to be a triggering event (Kischer, C.W., Speer, D.P. (1984). J. Hand. Surgery 9A: 58- 62), and an inflammatory mechanism may be involved (Baird, K.S., Alwan, W.H., Crossan, J.F., Wojciak, B (1993) Lancet 341 : 1622-1623).

The contraction in Dupuytrens is probably caused by contractile fibroblast-like cells called myofibroblasts, a phenotype common in wound healing (Gabbiani, G., Ryan, G.B., Majne, G. (1971). Experientia 27: 549-550). Molecular and pharmacological markers in these 'myofibroblasts' are intermediate between those of normal fibroblasts and those of smooth muscle cells: for example, myofibroblasts contain 'smooth muscle' subtype of α-actin (SMA-actin), but not other muscle-specific contractile proteins (Arora, P.D., McCulloch, C.A.G. (1994). J. Cellular Physiology 159: 161-175), myofibroblasts from Dupuytren's disease have a smooth-muscle-like contractile response to prostaglandins (Hurst, L.C., Badalamente, M.A., Makowski, J. (1986). J. Hand Surgery.11 A: 18-22), although they do not respond (as SMCs do) to 5- hydroxytryptamine.

Such myofibroblasts are characteristic of many diseases where a wound- response is generated inappropriately, particularly in other fibroses. An abnormal, proliferation of smooth muscle cells is also characteristic of some vascular diseases such as post-graft stenosis and re-stenosis following coronary artery angioplasty (Martin, J. (2000). Clinical and Experimental Allergy. 30: 33- 36). Summary of the Invention

This invention results from the realisation that agents which reduce/reverse the pathological wound-repair-related proliferation of contractile cells in vascular disease can also be used to prevent or reverse the differentiation and subsequent proliferation of myofibroblasts in Dupuytren's Contracture. Specifically, agents which have a cytoprotective effect on the vascular endothelium can be used to reduce or prevent the development of Dupuytren's Contracture. The present application discloses a method for retarding the development of Dupuytren's Disease and Dupuytren's Contracture by the treatment of actually or potentially affected areas with a therapeutic agent which is a cytoprotective agent for endothelial cells. Such an agent is a member of the Vascular Endothelial Growth Factor family of gene products. Without being bound by theory, it is expected that treatment of Dupyutren's contracture with such agents will reduce the development of the disease through renormalising the phenotype of the myofibroblasts that cause the disease. The treatment described in this invention is therefore expected to be most effective if used very early in the disease, or immediately after the bulk of the myofibroblasts have been removed by surgery, radiation therapy or other ablative treatment. Description of the Invention

While not wishing to be bound by theory, the present invention is based on the realisation that Dupuytren's Disease is caused primarily by the proliferation and contraction of myofibroblasts, that myofibroblasts are one cell type in a continuum of cell types that have fibroblasts at one extreme and smooth muscle cells at the other, and that therefore agents which are observed to regulate the proliferation of smooth muscle cells may act to prevent the abnormal proliferation of other cell types in this continuum, including myofibroblasts.

One group of such agents are the vascular endothelial gene family protein products, which act on endothelial cells which in turn act on smooth muscle cells in the walls of blood vessels. This invention is based on the understanding that, because Dupyutren's Disease is triggered in part by damage to the palmar microvasculature, agents which have this effect on endothelial cells will have a preventative effect on the development of Dupuytren's Disease. The term "Dupuytren's Disease" and "Dupuytren's Contracture" are used interchangeably herein.

"Contractile cells" are those cells that fall within the continuum of fibroblasts at one end and smooth muscle cells at the other end. The agents intended for use in the present invention will reduce/reverse the proliferation of such cells in vascular disease.

Therapeutic agents useful for this invention include VEGF-A, VEGF-B, VEGF-C etc.. Specific examples of these proteins (described by their NCBI database accession numbers) include P15692 (amino acids 27 through 232), CAA 09179, AAD55345, P49765 (amino acids 22-207), S69207 (amino acids 103-419), P97946 (amino acids 94-210), AAL27435 AAD03735, P52584 (amino acids 21-132) and CAA44447, and sequence variants and splice variants of these. Other proteins with similar biological function but different sequence will also be useful for this invention. A DNA sequence which causes the cell to produce such a protein is also a therapeutic agent useful for this invention: such agents may code for the protein themselves, or induce the cells into which they are put to synthesise the protein from their own gene or genes. A peptide which is designed to have the same biological effect as the proteins is also a useful therapeutic for this invention. A non-peptide small molecule is also a useful therapeutic for this invention. The method for designing or identifying a peptide or a small molecule which has the same effect as a protein, through structure- based chemical design or through a variety of combinatorial chemistry and screening processes, is well known to the skilled man.

The therapeutic agent will typically be targeted to the site of the Dupuytren's Disease. This may be done by local physical delivery (for example by injection or implantation), or by physically or chemically associating it with an agent which preferentially localises to the site of disease, for example an antibody or a liposome. The amount of therapeutic agent so delivered can readily be determined by the skilled man, having regard to conventional factors such as the condition of the patient, the severity of the problem to be treated, the potency of the agent and the desired effect. By way of example only, a suitable amount for administration is 0.1 picograms to 1 milligram per disease site. The therapeutic agent is preferably delivered to the site of the

Dupuytren's Disease. Most preferably, it is delivered to the site of disease immediately after corrective surgery, when the disease burden is minimal and the site is open for physical access. The agent may also be delivered through the blood vessels, by systemic injection, local injection, or by means of a stent, catheter or other device.

The therapeutic agent may be delivered as a solution which can be injected, sprayed or otherwise mechanically delivered, impregnated into a gel, tissue or other material which is implanted in the site as a sheet, as particles or in other physical form, or pre-loaded into cells which are then implanted by any method into the site of disease.

Claims

1. Use of an agent that reduces the wound-repair-related proliferation of contractile cells in vascular disease, in the manufacture of a medicament for the treatment of Dupuytren's disease or contracture.

2. Use according to claim 1 , wherein the agent is or encodes a member of the Vascular Endothelial Growth Factor family, or a fragment thereof which retains biological function.

3. Use according to claim 1 or claim 2, wherein the agent is or encodes VEGF-A, VEGF-B, VEGF-C or VEGF-D or a fragment thereof which retains biological function.

4. A method for the treatment if Dupuytren's disease or contracture, comprising administering to a patient a medicament as defined in any of claims 1 to 3.