Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-08-25
2001-11-20
Clark, Deborah J. R. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S002600, C530S300000, C530S350000
Reexamination Certificate
active
06319907
ABSTRACT:
The present invention relates to the healing of wounds.
Wound healing in adult tissues is a complicated reparative process. In skin for example the healing process involves the recruitment of a variety of specialised cells to the site of the wound, extracellular matrix and basement membrane deposition, angiogenesis, selective protease activity and re-epithelialisation.
There is a need to provide medicaments that promote the healing of wounds. For example, it is often desirable to increase the rate of healing in the case of acute wounds (such as penetrative injuries, burns, nerve damage or even wounds resulting from elective surgery), chronic wounds (such as diabetic, venous and decubitus ulceration) or for generally healing compromised individuals (for example the elderly). In these examples, the wounds can severely influence quality of life or even result in death and therefore the rate of healing often needs to be increased as much as is clinically possible.
The term “wounds” as used herein is exemplified but not limited to injuries to the skin. Other types of wound can involve damage, injury or trauma to an internal tissue or organ such as the lung, kidney, heart, gut, tendons or liver.
There have been several recent developments in the wound healing field. Some of these developments revolve around the recent understanding that growth factors are intimately involved in the repair of wounded tissue. In particular, members of the Transforming growth Factor &bgr; (TGF-&bgr;) superfamily have been found to play an important role in wound healing. At least 25 molecules are known to be members of the TGF-&bgr; superfamily. These include a number of cytokines such as TGF-&bgr;s 1 to 5, the DVR group (e.g. dpp and Vg1), Bone Morphogenetic Proteins, Nodal, Activin and Inhibin.
TGF-&bgr; (and other members of the superfamily) are secreted from cells as a pro-protein which is known as latent TGF-&bgr;. The pro-protein consists of an N terminal Latency Associated peptide (LAP) and the TGF-&bgr; and is referred to as the Small Latent Complex. Additionally the Small Latent Complex can bind to another peptide (derived from a different gene) of variable size called Latent TGF-&bgr; Binding Protein (LTBP) in which case the entire complex is known as the Large Latent TGF-&bgr; Complex.
Upon secretion of the pro-protein into the extracellular environment, proteolytic cleavage of LAP (and LTBP) from TGF-&bgr; can occur. However, TGF-&bgr; may remain non-covalently associated with LAP. TGF-&bgr; is activated when it is caused to be dissociated from the LAP. This dissociation may be coordinated at a mannose-6-phosphate/Insulin Like Growth Factor II receptor (M6P-R) and involve proteases such as plasmin, the substrates being associated at the cell surface by tissue transglutaminase. Free radicals and reactive oxygen species can also activate TGF-&bgr; by causing dissociation from the LAP.
TGF-&bgr; (particularly TGF-&bgr;1 and TGF-&bgr;2) promotes wound healing but is also associated with increased scar formation and fibrosis. In fact, clinical interest in the modulation of TGF-&bgr; has been associated with inhibiting its activity in order to reduce scar formation (although this may compromise the rate of wound healing). For instance, WO 92/17206 discloses compositions which inhibit the activity of TGF-&bgr;1 and TGF-&bgr;2 and are particularly beneficial for reducing scar formation.
Another development in the field involves the use of mannose-6-phosphate for use in treating fibrotic disorders associated with elevated levels of TGF-&bgr; (GB 2,265,3 10). Mannose-6-phosphate is believed competitively to interfere with the liberation of TGF-&bgr; from LAP at the M6P-R thereby inhibiting TGF-&bgr; activation and preventing fibrosis or scarring.
WO 91/08291 and WO 94/09812 relate to the role of LAP in modulating TGF-&bgr; activity and disclose methods of producing LAP and large latent TGF-&bgr; respectively. These documents also provide uses of LAP for antagonising or neutralising TGF-&bgr; activity by binding to TGF-&bgr; and reverting it back to a latent state. It is claimed that a consequence of this antagonism is to reduce scarring following wounding.
According to a first aspect of the present invention there is provided the use of Latency Associated Peptide, or a functional analogue thereof, for the manufacture of a medicament for increasing the rate of wound healing.
According to a second aspect of the present invention, there is provided a method of increasing the rate of wound healing comprising applying to the site of the wound a therapeutically effective amount of Latency Associated Peptide or functional analogue thereof.
The Latency Associated Peptide (LAP) used according to the invention is the N terminal region of the pro-proteins of the Transforming Growth factor &bgr; (TGF-&bgr;) superfamily of molecules, the said region being capable of maintaining at least one of the members of the TGF-&bgr; superfamily in a latent state. It is preferred that the LAP is capable of maintaining a TGF-&bgr; in a latent state and most preferred that the LAP will maintain TGF-&bgr;1 and/or TGF-&bgr;2 in a latent state.
In accordance with the invention, the inventors have established that LAP may be used to increase the rate at which a wound will heal. For example, in skin, we have found that LAP, or a functional analogue thereof, increases the rate of dermal healing (i.e. an open wound closes quicker when LAP is applied to the wound). This increase in the rate of healing can be further characterised by any of: an increase in the recruitment of a variety of specialised cells to the site of the wound (fibroblasts, leukocytes etc), an increase in extracellular matrix and basement membrane deposition, increased angiogenesis, increased selective protease activity and quicker re-epithelialisation.
This is a surprising development in the light of conventionally accepted interactions of TGF-&bgr; and LAP which are discussed above. According to the teaching of the prior art, LAP would be expected to antagonise or neutralise the effects of TGF-&bgr; and thereby reduce scarring and/or fibrosis. Conventionally such an effect would also be expected to result in a reduction in the rate of wound healing (e.g. slower closing of a incisonal wound of the skin).
The invention has been based on the inventors' studies which have shown that LAP, contrary to expectations, increases the rate of wound healing. These findings led to the realisation that LAP actually promotes the wound healing effects of TGF-&bgr; (and related molecules) and, at least with respect to wound healing, does not neutralise or antagonise TGF-&bgr; as suggested by WO 91/08291.
Although the inventors do not wish to be constrained by any hypothesis, they believe it is possible that the mechanism by which LAP is effective in increasing the rate of wound healing is by binding to TGF-&bgr; and protecting it from proteolytic degradation. This results in the sequestration of the active TGF-&bgr; (particularly TGF-&bgr;1 and TGF-&bgr;2) which is normally present during wound healing. This sequestered TGF-&bgr; may then act as a reserve which may be released into the wound and will effectively increase the half life of TGF-&bgr; over which time it promotes healing.
We have found that administration of LAP offers advantages over the use of exogenous TGF-&bgr; for increasing the rate of wound healing. Administration of exogenous doses of TGF-&bgr; can lead to inappropriately high localised concentrations of TGF-&bgr; which, as TGF-&bgr; increases the rate of wound healing and induces scarring or fibrosis, can cause unacceptable scarring or fibrosis. Administration of LAP, or a functional analogue thereof, has no such adverse effect and only modulates the activity of endogenously present TGF-&bgr;. Thus LAP, or a functional analogue thereof, is particularly useful for increasing the rate of wound healing without causing inappropriate scarring or fibrosis.
We have established that LAP, and functional analogues thereof, increases the rate of wound healing of a v
Clark Deborah J. R.
Nixon & Vanderhye P.C.
Renovo Limited
Sorbello Eleanor
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