Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
1994-09-16
2001-12-18
Nolan, Patrick J. (Department: 1644)
Drug, bio-affecting and body treating compositions
Lymphokine
C424S145100, C424S158100
Reexamination Certificate
active
06331298
ABSTRACT:
This invention concerns the healing of wounds and other conditions in which fibrosis is a major mechanism of tissue repair or where excessive fibrosis leads to pathological derangement and malfunctioning of the tissues. It refers in particular to agents and techniques for facilitating repair and healing of animal tissues, without excessive fibrosis, and for preventing or treating diseases and conditions of fibrosis.
Fibrosis is a major problem in wound healing causing scarring of the tissue, which not only looks unsightly, but also causes problems in respect of growth of the tissue, function, movement etc. This is particularly true following injuries to children or following major burns.
In addition, fibrosis is a major medical problem where abnormal or excessive deposition of fibrous tissue occurs in many diseases, including liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoid arthritis, as well as wound healing.
The mechanism of fibrosis is still not fully understood, but wound healing usually begins as an inflammatory reaction with leucocyte infiltration and accumulation of cytokines. These cytokines are responsible for the proliferation of fibroblasts and the deposition of extracellular matrix proteins (including collagen and fibronectin) which accumulate and result in permanent alteration in tissue structure and function.
Examples of the regulatory cytokines include tumor necrosis factor (TNF), fibroblast growth factors (FGF's), platelet derived growth factor (PDGF) and transforming growth factor &bgr; (TGF&bgr;), (TGF&bgr;-1 to TGF&bgr;-5 have so far been identified). Two of these cytokine families TGF&bgr; and PDGF, have been reported to be highly fibrogenic, and, moreover, inhibition of two of the TGF&bgr;'s and PDGF activity, using anti-TGF&bgr;-1, anti-TGF&bgr;-2 and anti-PDGF antibodies, has been shown to diminish fibrosis in tissue injury (Shah el al, The Lancet, 339, 213-214, 1992; WO 91/04748).
The present invention provides novel compositions useful in the treatment of wounds and fibrotic disorders and which may prevent, inhibit or reverse fibrosis.
The invention comprises a healing composition containing at least one non-fibrotic growth factor in combination with a pharmaceutically acceptable carrier.
The composition may comprise TGF&bgr;-3 as the or a non-fibrotic growth factor, such that on application of the composition to the tissue, this non-fibrotic growth factor is present in an elevated level compared to its naturally occuring level.
The composition may comprise acidic or basic FGF as the or a non-fibrotic growth factor, again resulting in a much elevated level of non-fibrotic growth factor than would naturally be present.
The composition may comprise anti-fibrotic agents, such as fibrotic growth factor neutralising agents, for example antibodies to TGF&bgr;-1, TGF&bgr;-2 and PDGF; binding proteins which prevent TGF&bgr;-1, TGF&bgr;-2 and PDGF from binding to their receptors by either binding to the growth factor itself, eg. Decorin, Biglycan, or binding to the receptor, eg. peptides containing the receptor binding site sequence or soluble forms of the growth factor receptors and the growth factor binding domains of these receptors; and antisense oligo-nucleotides or ribosymes which act to prevent fibrotic growth factor mRNA translation.
The composition may comprise combinations of non-fibrotic growth factors, for example, TGF&bgr;-3 and anti-fibrotic agents, for example, anti-TGF&bgr;-1 and anti-TGF&bgr;-2.
The non-fibrotic growth factor and/or anti-fibrotic agent(s) may be present in the composition in an active or inactive form. Inactivation may be by any of a number of mechanisms, for example, by encapsulation. Capsules may be degradeable by an external stimulus to release the active form when required. The external stimulus may include UV light, ultrasound, in vivo enzymes or heat.
Inactivation may, however, be by the molecular addition of a binding molecule. The binding molecule may be detachable when required by an external stimulus such as UV light, ultrasound, in vivo enzymes or heat.
The non-fibrotic growth factor may be present in an inactive form, for example, as a precursor, and may be activated upon contact with tissue containing the natural cleavage enzymes required to convert the precursor into its active form.
The carrier may comprise a neutral sterile cream, gel, aerosol or powder for topical application, or may be in the form of a patch, sterile dressing or an absorbable dressing. The carrier may be a biopolymer of collagen, hyaluronic acid or polymer of PVC to which the anti-fibrotic or non fibrotic agents are attached in such a way as to facilitate their action and/or release when the carrier is in contact with or implanted into either the wound or fibrotic lesion. The carrier may also comprise a sterile solution for irrigation, injection either locally or systemically or inhalation, or may be in the form of a tablet, capsule, and the like, for enteral administration.
The present invention also provides a method of preparation of a pharmaceutical healing or anti-fibrotic composition containing at least one non-fibrotic growth factor for topical application in a cream, gel, aerosol, powder, patch, dressing, biopolymer or polymer implant, delay or slow release system, or in a solution for irrigation, injection or inhalation, or in a tablet or capsule for enteral administration.
The present invention also provides a method of inhibiting fibrosis during the healing of wounds and in other fibrotic conditions and disorders, for example ulcers, comprising administering to a host suffering from tissue wounding or other fibrotic conditions and disorders, at least one non-fibrotic growth factor.
The present invention also provides a method of reversing fibrosis in such fibrotic conditions and disorders comprising administering to a host suffering from such fibrotic conditions and disorders, at least one non-fibrotic growth factor, for example, TGF&bgr;-3 and/or at least one anti-fibrotic agent for example, anti-TGF&bgr;-1/TGF&bgr;-2.
As mentioned above, two cytokines have been identified as being involved in fibrosis, namely PDGF and TGF&bgr;. Of these two, TGF&bgr; appears to play the major role. For example, in tissues which heal without scar formation, such as fetal and embryonic wounds where there is a lowered inflammatory response and altered cytokine profile, the level of TGF&bgr; in particular, is much reduced.
TGF&bgr; comprises a family of molecules, the important mammalian members being TGF&bgr;-1, TGF&bgr;-2 and TGF&bgr;-3 (Roberts and Sporn, The Transforming Growth Factor-&bgr;s, In: Peptide Growth Factors and their Receptors, Springer Verlag, Berlin, 1990, p418-472). The TGF&bgr;s, although having different patterns of expression, share over 70% peptide homology and are thought to have similar functions and act inter-changeably. Thus in wound healing it would be expected that TGF&bgr;-3 would act like TGF&bgr;-1 and TGF&bgr;-2 to increase extracellular matrix production, angiogenesis and the inflammatory response.
As discussed above, fibrotic disease is a major medical problem. In such diseases, there is abnormal or excessive deposition of fibrous tissue. Such diseases are exemplified by liver cirrhosis, glomerulonephritis, pulmonary fibrosis, systemic fibrosis and rheumatoid arthritis. In such diseases the use of TGF&bgr; would be avoided, since TGF&bgr;'s are believed to increase the deposition of fibrous tissue. Suprisingly, it has now been discovered that TGF&bgr;-3 has the opposite effect to that expected, in that it promotes healing without promoting the deposition of fibrous tissue.
The present invention provides the use of a TGF&bgr;-3 for the manufacture of a medicament for the treatment of a fibrotic disease.
The present invention also provides a method of treating a fibrotic disease by administering a pharmaceutically effective amount of TGF&bgr;-3 to a patient in need thereof.
The present invention also provides an agent for treating a fibrotic disease which comprises
Ferguson Mark William James
Shah Mamta
Nixon & Vanderhye P.C.
Nolan Patrick J.
Renovo Limited
LandOfFree
Wound healing and treatment of fibrotic disorders does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Wound healing and treatment of fibrotic disorders, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Wound healing and treatment of fibrotic disorders will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2558179