Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• Preferred fragments may include amino acid residues involved in binding of WNT5 A to its cellular receptors.
• WNT5A is able to signal through a number of receptors, or receptor complexes.
• Fz5 acts as a receptor for WNT5A
• WNT5A is capable of inducing signalling via a Fz4/LRP5 complex, or an orphan tyrosine kinase receptor, Ror2 (He, et al. 1997; and Mikels and Nusse 2006).
• it is the three dimensional structure of WNT5A that is important in considering receptor binding, and that accordingly suitable fragments may be selected based upon their ability to assume the requisite three dimensional conformation necessary for receptor binding.
• the thickness of ECM fibres and orientation of ECM fibres may be favoured parameters, for assessing inhibition of scarring.
• a treated scar may preferably have improved ECM orientation (i.e. orientation that is more similar to unwounded skin than is the orientation in an untreated scar).
• inhibition of scarring of a treated wound may be indicated by improvement of one or more of such suitable parameters, and that in the case of inhibition as assessed with reference to a number of parameters that these parameters may be combined from different assessment schemes (e.g. inhibition as assessed with reference to at least one parameter used in macroscopic assessment and at least one parameter used in microscopic assessment).
• Inhibition of scarring may be demonstrated by an improvement in one or more parameters indicating that a treated scar more closely approximates unscarred skin with reference to the selected parameter(s) than does an untreated or control scar.
• Suitable parameters for the clinical measurement and assessment of scars may be selected based upon a variety of measures or assessments including those described by Beausang et al (1998) and van Zuijlen et al (2002).
• the height and width of scars can be measured directly upon the subject, for example by use of manual measuring devices such as callipers.
• Scar width, perimeter and area may be measured either directly on the subject, by image analysis of photographs of the scar, or on plaster casts of impressions of the scar.
• image analysis of photographs of the scar or on plaster casts of impressions of the scar.
• the skilled person will also be aware of further non-invasive methods and devices that can be used to investigate suitable parameters, including silicone moulding, ultrasound, optical three-dimensional profilimetry and high resolution Magnetic Resonance Imaging.
• Inhibition of scarring may be demonstrated by a reduction in the height, width, area, perimeter or volume, or any combination thereof, of a treated scar as compared to an untreated scar.
• the appearance or colour of a treated scar may be compared to that of surrounding unscarred skin, and the differences (if any) compared with the difference between the appearance and colour of untreated scars and unscarred skin. Such a comparison may be made on the basis of a visual assessment of the respective scars and unscarred skin.
• the appearance of a scar may be compared with unscarred skin with reference to whether the scar is lighter or darker, or redder, than the unscarred skin.
• the respective colours of the scars and skin may be perfectly matched to one another, slightly mismatched, obviously mismatched or grossly mismatched.
• Inhibition of scarring may be demonstrated by a smaller magnitude of difference between the appearance or colour of treated scars and unscarred skin than between untreated scars and unscarred skin.
• Scar contour may be investigated by means of visual assessment. Suitable parameters to consider in such an assessment include whether or not a scar is flush with surrounding skin, slightly proud, slightly indented, hypertrophic or keloid. The texture of a scar may be assessed with reference to the scar's appearance, and this may also be undertaken by a visual assessment as to whether the scar is, for instance, matt or shiny or has a roughened or smooth appearance as compared to unscarred skin.
• Scar texture may additionally be assessed with reference to whether the scar has the same texture as unscarred skin (normal texture), is just palpable, firm or hard compared to unscarred skin.
• the texture of scars may also be assessed with reference to the Hamilton scale (described in Crowe et al, 1998).
• non-invasive profilimetry devices that use optical or mechanical methods for assessment of scar contour and/or texture.
• assessments may be carried out on the body of the subject or, for example, on silicone mould impressions of scars, or on positive casts made from such impressions.
• Photographic assessment of treated and untreated scars may be performed by an independent lay panel of assessors using standardised and calibrated photographs of the scars.
• the scars may be assessed by an independent lay panel to provide categorical ranking data (e.g. that a given treated scar is "better”, “worse” or “no different” when compared to an untreated scar) and quantitative data using a Visual Analogue Scale (VAS) based upon the method described by Beausang et al. (1998).
• VAS Visual Analogue Scale
• Photographic assessment of treated and untreated scars may alternatively or additionally be performed by a panel of expert assessors using standardised and calibrated photographs of the scars to be assessed.
• the panel of experts may preferably consist of individuals skilled in the art, suitable examples of which include plastic surgeons and scientists having relevant technical backgrounds.
• Such assessment may provide categorical data, as described above, or with respect to the comparison of a time-course of images of selected treated and untreated scars.
• Suitable assessments that may be useful in assessing inhibition of scarring include:
• the best scar may be considered to be the one which most closely resembles the surrounding skin.
• the magnitude of the difference between scars may be considered, for example, whether the difference between scars is slight or obvious. Further parameters that may be considered include the earliest time after scar formation at which a difference between scars may be detected, the time post- formation at which the difference between scars is most obvious (or alternatively the finding that the difference continues after the last timepoint assessed), as well as considering whether or not the better scar remains consistently better.
• An expert panel may also consider whether or not one of a treated or untreated scar is consistently paler than the other, or paler than unscarred skin, hi the event that a difference in paleness is detectable consideration may be given to the time after scar formation at which the difference may be detected, the time at which the difference is most obvious, and the time at which the difference disappears.
• a further parameter that may be assessed by an expert panel is the texture of treated and untreated scars.
• the expert panel may consider which of the scars has the texture most similar to that of unscarred skin, the earliest time after scar formation at which any difference in texture may be detected, the time post formation at which any difference is most obvious, and the time at which any difference disappears
• Comparison of treated and untreated scars may further assess which of the scars is narrowest, and which of the scars is shortest. Consideration may also be given to the shape of the scar and the proportion of the scar margin that is distinguishable from the surrounding skin. As with previously described visual assessments and assessments of colour, the presence, degree and location of hyper-pigmentation may also be considered. Clinical assessment
• a clinician investigator or not, or an independent panel of clinicians may assess the scar(s) on a patient using any of the forgoing parameters e.g. VAS, colour, categorical scales etc.
• the patient may assess their own scars and/or compare scars by means of a structured questionnaire.
• This questionnaire may measure their satisfaction with the scar, how well the scar blends with the surrounding skin, as well as the effect of the scar on their daily life e.g. do they hide it with clothes, avoid exposing it; as well as scar symptoms e.g. itch, pain, paresthesia.
• Inhibition of scarring may be determined by the treated scar being rated better, causing the patient fewer problems, causing fewer and less scar symptoms, and with an increase in patient satisfaction compared to an untreated scar.
• microscopic assessment of scar quality may typically be carried out using histological sections of scars.
• the process of microscopically assessing and measuring scars may take into consideration categorical data based on the following suitable parameters:
• Collagen organisation In assessing collagen organisation reference may be made to the orientation of collagen fibres present in the scar, the density of such fibres and collagen fibre thickness in the papillary and reticular dermis. An inhibition of scarring may be indicated when a treated scar contains collagen organisation that more closely approximates that found in unwounded skin than does the organisation in untreated or control treated scars.
• Angiogenesis and Inflammation may be given to the number of blood vessels present, the size of the blood vessels present and evidence of inflammation, including an assessment of any level of inflammation present.
• An inhibition of scarring may be indicated when a treated scar contains blood vessels and inflammatory cells in quantities and arrangements that more closely approximate those found in unwounded skin than those found in untreated or control treated scars.
• quantitative data (preferably relating to the above parameters) can be generated using image analysis in combination with suitable visualisation techniques.
• suitable visualisation techniques that may be employed in assessing scar quality are specific histological stains or immuno-labelling, wherein the degree of staining or labelling present may be quantitatively determined by image analysis
• Quantitative data may be usefully and readily produced in relation to the following parameters:
• ECM molecules e.g. elastin, fibronectin
• inhibition of scarring may be demonstrated with reference to more than one parameter. More preferably inhibition of scarring may be demonstrable with reference to both a clinical (i.e. observed on the subject) parameter and a photographic parameter. Even more preferably inhibition of scarring may be demonstrable with reference to a clinical parameter, a photographic parameter, and also a microscopic assessment parameter (for instance a histological parameter). Most preferably inhibition of scarring may be demonstrable with reference to a clinical VAS score, external lay panel VAS score and ranking (from photographic images) and microscopic VAS score of the reticular dermis.
• skin scarring is responsible for a number of deleterious effects afflicting those suffering from such scarring.
• skin scarring may be associated with reduction of physical and mechanical function, particularly in the case of contractile scars (such as hypertrophic scars) and/or situations in which scars are formed across joints.
• contractile scars such as hypertrophic scars
• scars are formed across joints.
• suitable medicaments and methods of the invention be used to inhibit scarring of wounds covering joints of the body.
• suitable medicaments and methods of the invention may be used to inhibit scarring of wounds at increased risk of forming a contractile scar.
• burns injuries may extend over great areas of an individual so afflicted. Accordingly, burns may give rise to scar formation covering a large proportion of a patienfs body. This great extent of coverage increases the risk that the scar formed will cover areas of elevated cosmetic importance (such as the face, neck, arms or hands) or of mechanical importance (particularly the regions covering or surrounding joints). Burns injuries caused by hot liquids are frequently suffered by children (for example as a result of upsetting pans, kettles or the like) and, due to the relatively smaller body size of children, are particularly likely to cause extensive damage over a high proportion of the body area. Furthermore, burns injuries, and particularly those suffered by children, have an elevated risk of producing pathological hypertrophic scars of the type described below. Such hypertrophic scars may increase both the cosmetic and mechanical ill-effects associated with scarring after burns.
• medicaments and methods of the invention be used to inhibit scarring resulting from bums injuries.
• the extent of scar formation, and hence extent of cosmetic or other impairment that may be caused by the scar may also be influenced by factors such as the tension of the site at which the wound is formed.
• suitable medicaments and methods of the invention may be used to inhibit scarring of wounds located at sites of high skin tension.
• such medicaments and methods of the invention be used to inhibit scarring of wounds during surgical revision of disfiguring scars.
• Pathological scarring may have more pronounced deleterious effects than arise even as a result of relatively severe normal scarring.
• Common examples of pathological scars include keloids, hypertrophic scars and pterygium.
• Keloid scars constitute a notable example of pathological scarring, and are raised scars that spread beyond the margins of the original wound and invade the surrounding normal skin. Keloids continue to grow over time, do not regress spontaneously, and frequently recur following surgical excision. Keloid scars occur with equal frequency in men and women, mainly from ages 10 to 30, and can result from piercing, surgery, vaccination, tattoos, bites, blunt trauma and burns. A number of studies have suggested that there is an underlying genetic predisposition to keloid formation since keloid scars are more prevalent in dark skinned races.
• Keloids appear as elevated scars that may typically be hyperpigmented or hypopigmented in relation to the surrounding tissue. Keloids may be characterised on the basis of their tendency to grow beyond the initial boundaries of a wound. At a microscopic level, keloids may be characterised by the presence of large whorls of collagen, and the predominantly acellular nature of the interior of the lesion.
• Scarring in the eye may be inhibited by medicaments of the invention.
• application of the medicament may be local e.g. local eye drops, sponge etc.
• Scarring may additionally be assessed by measuring the opacity, or transmitting/refractory properties, of the cornea e.g. using in vivo confocal microscopy.
• Scarring deeper in the eye e.g. at the retina may also be inhibited by the medicaments of the present invention delivered either locally or in devices or by injection.
• Scarring in the nervous tissue may be inhibited by the medicaments of the invention. Such scarring may arise as a result of surgery or trauma and may additionally be assessed by future assays of nerve function e.g. sensory or motor tests. Inhibitors of scarring should improve such future outcomes.
• Scarring in the blood vessels e.g. following anastomotic surgery can lead to myointimal hyperplasia and reduction in the volume of the blood vessel lumen. This can be measured directly e.g. using ultrasound, or indirectly be means of blood flow. Inhibition of scarring brought about by medicaments of the invention would lead to a reduction in blood vessel lumen narrowing (restenosis) and a more normal blood flow.
• Agents of the invention may be delivered to blood vessels by direct injection into the walls of the blood vessel before suturing, by bathing the anastomotic site in the agent or by local devices e.g. stents.
• Scarring in tendons and ligaments e.g. following surgery or trauma may be inhibited by medicaments of the invention. Inhibition of scarring may be measured in these terms by restoration of function e.g. ability to bear weight, stretch, flex etc.
• Preferred routes of administration by which therapeutically effective amounts of WNT5A, or fragments or derivatives thereof, are administered are discussed more fully elsewhere in the specification, but it may generally be preferred that these therapeutic molecules are provided by local administration to the wound the scarring of which is to be inhibited. Suitable methods by which such local administration may be achieved will depend on the identity of the tissue in question. Preferred routes of administration may include local injection (for example intradermal injection in the case where it is wished to inhibit dermal scarring). Other suitable means of administration include the use of topical medicaments such as sprays; powders; drops (e.g. for the ear or eye); ointments or creams; or release from local devices e.g. stents, implants, polymers.
• topical medicaments such as sprays; powders; drops (e.g. for the ear or eye); ointments or creams; or release from local devices e.g. stents, implants, polymers.
• Medicaments of the invention for the prevention and/or treatment of fibrotic disorders may be formulated and manufactured in any form that allows for the composition to be administered to a patient. Fibrotic disorders will frequently occur in relatively inaccessible tissues and organs, and it may be preferred that WNT5A, or its therapeutically effective fragments or derivatives, be administered systemically. Suitable routes of administration include, without limitation, oral, transdermal, inhalation, parenteral, sublingual, rectal, vaginal and intranasal.
• solid oral formulations such as tablets or capsules
• Aerosol formulations for inhalation may be preferred for the prevention and/or treatment of chronic obstructive pulmonary disease or other fibrotic disorders of the lungs and airways.
• routes of administration described above may also be suitable for topical administration to a tissue in which it is wished to prevent and/or treat a fibrotic disorder (for example, inhalation or intranasal for prevention and/or treatment of fibrosis associated with the respiratory system).
• a fibrotic disorder for example, inhalation or intranasal for prevention and/or treatment of fibrosis associated with the respiratory system.
• compositions that will be administered to the patient may preferably take the form of one of more dosage units providing a therapeutically effective amount, or a known fraction thereof. Methods of preparing such dosage forms will be well known to the skilled person; for example see Remington's Pharmaceutical Sciences 18 th Ed. (1990).
• a therapeutically effective amount of WNT5A, or its fragments or derivatives thereof, suitable for use in the methods or medicaments of the invention to prevent and/or treat a fibrotic disorder is an amount that is capable of reducing fibrosis (as assessed with reference to at least at least one of the parameters discussed below) associated with the fibrotic disorder.
• a therapeutically effective amount of WNT5A may be an amount that is effective to achieve a reduction of at least 10% compared to the level of fibrosis occurring in an untreated tissue subject to the fibrotic disorder.
• a therapeutically effective amount may be capable of achieving at least a 20% reduction in fibrosis, more preferably at least 50%, even more preferably at least 75% and most preferably at least a 90% reduction in fibrosis compared to a non-treated fibrotic tissue.
• Suitable parameters that may be assessed in the quantification of fibrosis associated with fibrotic disorders will be apparent to the skilled person. The following examples are provided by way of illustration only.
• Fibrosis associated with fibrotic disorders may classically be assessed with reference to trichrome staining (for example Masson's trichrome or Mallory's trichrome) of biopsy samples taken from a tissue subject to the fibrotic disorder. These samples may be compared with non-fibrotic tissues and reference tissues representative of staining in a range of tissues subject to fibrosis. Protocols for trichrome staining are well known to the skilled person, and kits that may be used to conduct trichrome staining are commercially available.
• trichrome staining for example Masson's trichrome or Mallory's trichrome
• biochemical markers of fibrosis for use as a non-invasive alternative to liver biopsy in patients with chronic hepatitis C or B, alcoholic liver disease and metabolic steatosis (for instance the overweight, patients with diabetes or hyperlipidemia).
• biochemical markers for use as a non-invasive alternative to liver biopsy in patients with chronic hepatitis C or B, alcoholic liver disease and metabolic steatosis (for instance the overweight, patients with diabetes or hyperlipidemia).
• these procedures are able to determine levels of liver fibrosis and necroinflammatory activity.
• the use of such tests is increasingly clinically accepted as an alternative to biopsies, and the tests are commercially available from suppliers such as BioPredictive.
• the methods or medicaments of the invention may be used prophylactically, i.e. prior to wounding that would otherwise lead to scar formation, or prior to the onset of a fibrotic disorder.
• this may involve administration of a therapeutically effective amount of WNT5A, or a therapeutically effective fragment or derivative thereof, at sites where no wound presently exists, but where a wound that would otherwise give rise to a scar is to be formed.
• medicaments in accordance with the invention may be administered to sites that are to undergo wounding as a result of elective procedures (such as surgery), or to sites that are believed to be at elevated risk of wounding.
• medicaments of the invention may be administered to a site at elevated risk of developing a fibrotic disorder prior to formation of said disorder.
• Suitable sites may be those that are perceived to be at elevated risk of the development of fibrotic disorders.
• An elevated risk of development of fibrotic disorders may arise as a result of disease, or as a result of environmental factors (including exposure to fibrotic agents), or as a result of genetic predisposition.
• the methods and medicaments of the invention may, for instance, preferably be administered within the first 24 hours after a wound is formed, but may still inhibit scarring if administered up to ten, or more, days after wounding.
• the methods and medicaments of the invention may be administered to a site at which a fibrotic disorder is already developing, in order to prevent further fibrosis taking place.
• This use will obviously be advantageous in situations in which the degree of fibrosis that has occurred prior to administration of WNT5A, or a therapeutically effective fragment or derivative thereof, is sufficiently low that the fibrotic tissue is still able to function.
• Medicaments of the invention may preferably be administered within 24 hours of the onset of fibrosis, but may still be effective if administered considerably later in the fibrotic process.
• medicaments may be administered within a month of the onset of fibrosis (or of the diagnosis that fibrosis is taking place), or within sixth months, or even one or more years, depending on the extent of fibrosis that has already occurred, the proportion of the tissue effected by the fibrotic disorder, and the rate at which the fibrotic disorder is progressing.
• the methods and medicaments of the invention may be administered on one or more occasions (as necessary) in order to inhibit scarring, and/or prevent and/or treat a fibrotic disorder.
• therapeutically effective amounts of the medicaments may be administered to a wound as often as required until the healing process has been completed.
• the medicaments of the invention may be administered daily or twice daily to a wound for at least the first three days following the formation of the wound.
• the inventors have found that regimes involving two administrations of medicaments of the invention, the first prior to formation of a wound and the second after wounding, are particularly beneficial in inhibiting scar formation.
• such regimes may involve a first administration immediately prior to formation of a wound and a second administration 24 hours after wounding.
• a therapeutically effective amount sufficient to prevent the onset or progression of a fibrotic disorder may be provided by means of a number of administrations. Suitable regimes may involve administration monthly, weekly, daily or twice daily.
• WNT5A therapeutically effective fragments or derivatives thereof
• a therapeutically effective amount of WNT5 A, its fragments or derivatives may be provided by means of any number of suitable administrations. Suitable regimes for these administrations may be readily devised by the skilled person using techniques (including in vitro studies, animal and human studies) well known in and established within the pharmaceutical industry.
• WNT5A or its therapeutically effective fragments or derivatives, may also be used in the treatment of existing fibrotic disorders in order to bring about a reduction in the extent of fibrosis associated with the disorder.
• Therapeutically effective amounts, and preferred administration regimes, for use in this manner may be determined as described elsewhere in the specification.
• agent or “agent of the invention” is meant WNT5A, or a therapeutically effective fragment of WNT5A, or a therapeutically effective derivative of WNT5A. It will be appreciated that all such agents may be incorporated in medicaments in accordance with the invention, and all may be used in the methods or uses of the invention.
• the medicaments of the invention represent preferred compositions by which WNT5A, or its therapeutically effective fragments or derivatives, may be administered in order to put the methods of the invention into practice.
• the amount of a medicament of the invention that should be provided to a wound or fibrotic disorder, in order that a therapeutically effective amount of WNT5A, its fragments or derivatives, may be administered depends on a number of factors. These include the biological activity and bioavailability of the agent present in the medicament, which in turn depends, among other factors, on the nature of the agent and the mode of administration of the medicament. Other factors in determining a suitable therapeutic amount of a medicament may include:
• B) The specific condition to be treated e.g. acute wounding or chronic fibrotic disorders.
• the frequency of administration will also be influenced by the above-mentioned factors and particularly the half-life of the chosen agent within the subject being treated.
• medicaments in accordance with the invention when used to treat existing wounds or fibrotic disorders the medicament should be administered as soon as the wound occurs or the fibrotic disorder begins. In the case of wounds or fibrotic disorders that are not immediately apparent, such as those at internal body sites, medicaments may be administered as soon as the wound or disorder is diagnosed. Therapy with methods or medicaments in accordance with the invention should continue until scarring has been inhibited, or the fibrotic disorder prevented or treated, to a clinician's satisfaction.
• Medicaments of the invention may be administered by any suitable route capable of achieving the desired effect of inhibiting scarring or treating fibrosis, but it is preferred that the medicaments be administered locally at a wound site or site of a fibrotic disorder.
• a preferred medicament in accordance with the invention comprises an injectable solution of an agent of the invention (e.g. for injection around the margins of a wound, or a site likely to be wounded). Suitable formulations for use in this embodiment of the invention are considered below.
• medicaments of the invention may also be administered in a topical form to inhibit scarring or treat a f ⁇ brotic disorder.
• such administration may be effected as part of the initial and/or follow up care for the wounded area.
• the vehicle of a composition comprising agents of the invention should be one that is well tolerated by the patient and allows release of the agent to the wound or fibrotic site.
• a vehicle is preferably biodegradeable, bioresolveable, bioresorbable and/or non-inflammatory.
• Medicaments and compositions comprising agents of the invention may be used in a number of ways.
• a composition may be applied in and/or around a wound or fibrotic disorder in order to inhibit scarring or treat fibrosis. If the composition is to be applied to an existing wound or fibrotic site, then the pharmaceutically acceptable vehicle will be one which is relatively "mild" i.e. a vehicle which is biocompatible, biodegradable, bioresolvable and non-inflammatory.
• the amount of WNT5A, or a therapeutically effective fragment or derivative thereof, to be administered via topical administration may be altered depending on permeability of the tissue or organ to which the topical composition is administered.
• Such an increased amount of WNT5 A, or a therapeutically effective fragment or derivative thereof may still represent a therapeutically effective amount, if the amount of the agent taken up into the tissue or organ to be treated is therapeutically effective (i.e. if a therapeutically effective amount permeates the tissue or organ to be treated, irrespective of the fact that a larger, non- therapeutic, amount of the agent may remain on the surface of, and unable to penetrate, the tissue or organ being treated).
• the amount of WNT5 A, or a therapeutically active fragment or derivative thereof, to be administered to a wound or site of fibrosis in a single incidence of treatment will preferably not exceed 21 pmoles/cm of wound, or cm 2 of fibrosis. More preferably the amount administered in a single incidence of treatment will be less than 21 pmoles/cm of wound, or cm 2 of fibrosis.
• the total amount of WNT5A, or a therapeutically active fragment or derivative thereof, that may be administered by local injection to a wound or site of fibrosis may be preferably be in the region of 0.01 - 44 pmoles/centimetre of wound or cm 2 fibrosis.
• the total amount of WNT5 A, or a therapeutically active fragment or derivative thereof, that may be administered by local injection to a wound or site of fibrosis may be preferably be in the region of 0.022 - 0.44 pmoles/centimetre of wound or cm 2 fibrosis.
• a suitable amount to be administered may be in the region of 0.01 - 44 pmoles/cm of wound or cm 2 or fibrosis.
• a suitable amount to be administered may be in the region of 0.022 - 0.44 pmoles/cm of wound or cm 2 or fibrosis.
• the WNT5A, or therapeutically active fragments or derivatives thereof may more preferably be administered as a 0.11 nM to 165 nM solution. lOO ⁇ L of such a solution may be administered per centimetre of wound or cm 2 of fibrosis over a 24 hour period. Most preferably the WNT5A, or therapeutically active fragments or derivatives thereof, may be administered as a 0.11 nM; 2.2 nM; or 165 nM solution with lOO ⁇ L of such a solution administered per centimetre of wound or cm 2 of fibrosis over a 24 hour period.
• WNT5A therapeutically effective dosages set out herein will provide sufficient guidance to allow the skilled person to calculate the local concentrations of WNT5A, or its therapeutically effective fragments or derivatives, established by intradermal injection, and, based on these values, to determine suitable amounts of such agents that may be administered by other routes in order to achieve equivalent local concentrations.
• WNT5A may be administered by way of an injectable solution containing between 0.5ng/100 ⁇ L and 750ng/100 ⁇ L of an agent of the invention in order to inhibit scarring or treat fibrosis when administered as an intradermal injection providing lOO ⁇ iL of solution per cm of wound margin or cm 2 of fibrosis.
• Nucleic acids for use in this embodiment of the invention may be administered "as is", for example by means of ballistic transfection, or as parts of a larger construct, which may be able to incorporate stably into cells so transfected.
• Suitable constructs may also contain regulatory elements, by which expression of a therapeutically effective amount of WNT5 A, or a fragment or derivative thereof, may be achieved.
• the Sequence Information section shows the amino acid sequence of human WNT5A (shown as Sequence ID NO. 1), and the sequence of cDNA encoding human WNT5A (shown as Sequence ID No. 2).
• Figure 1 compares macroscopic VAS scores of treated scars, untreated scars and control treated scars. Results are shown in the form of a bar chart showing macroscopic VAS scores for scars formed 70 days after wounding. "**” indicates/* ⁇ 0.01 versus na ⁇ ve and diluent controls. "*” indicates p ⁇ 0.05 versus na ⁇ ve and diluent control. " x” indicates p ⁇ 0.05 versus diluent control only (not na ⁇ ve control)
• Figure 2 compares microscopic VAS scores of treated scars, untreated scars and control treated scars. Results are shown in the form of a bar chart showing microscopic VAS scores for scars formed 70 days after wounding. "**” indicates p ⁇ 0.01 versus na ⁇ ve and diluent control. “*” indicates p ⁇ 0.0l versus na ⁇ ve control only (not diluent control).
• Figure 3 shows illustrative macroscopic images of a treated scar (Panel A); and an untreated scar (Panel B).
• the photographs show macroscopic appearance of scars 70 days after incision.
• the scar in panel A was treated with WNT5A at a concentration of lOng/lOO ⁇ l, while the wound producing the scar shown in panel B was untreated (na ⁇ ve wound).
• Figure 4 shows illustrative macroscopic images of treated scars (Panels A, B and C); and a control treated scar (Panel D).
• the photographs show macroscopic appearance of scars 70 days after incision.
• the wounds have been treated with lng/lOO ⁇ l WNT5A, lOng/lOO ⁇ l WNT5A or lOOOng/lOO ⁇ l WNT5A, or with diluent alone, as shown in the captions.
• Figure 5 shows illustrative microscopic images comparing scars produced on healing of control treated wounds and wounds treated with different amounts of WNT5A (including both therapeutically effective amounts and non-therapeutically effective amounts). Images were taken from cutaneous scars of rats 70 days post-wounding and treatment. The images were taken, at x5 magnification, from histological sections of scars stained with Masson's Trichrome. Arrows indicate the edges of resultant scars following full thickness incisional wounding and treatment. 'S' indicates the scar, 'ND' indicates the normal surrounding dermis.
• the inventors investigated the effects of WNT5A on scarring using in an in vivo model of scar formation and healing.
• Recombinant mouse WNT5A (Catalogue number #645-WN/CF; Lot MCR074091) was purchased from R&D Systems.
• PBS alone was used as a diluent control.
• Treated and control-treated wounds were re-treated day 1 post-wounding with the appropriate treatment via injection of 50 ⁇ l to each of the two margins of the wound.
• each injection of the lng/lOO ⁇ l solution provided 0.022pmoles of WNT5A
• each injection of the lOng/lOO ⁇ l solution provided 0.22pmoles of WNT5A
• each injection of the lOOOng/lOO ⁇ l solution provided 22pmoles of WNT5A.
• Diluent control treated wounds received PBS alone (administered in the same volume and by the same route as WNT5A solutions in treated wounds), and the na ⁇ ve control wounds received no treatment.
• VAS visual analogue scale
• the best scars (typically of small width with colour, height and contour like normal skin) were scored towards the normal skin end of the scale (the left hand side of the VAS line) and bad scars (typically large width, raised with uneven contours and whiter colour) were scored towards the bad scar end of the scale (the right hand side of the VAS line).
• the marks were measured from the left hand side to provide the final value for the scar assessment in centimetres (to 1 decimal place).
• VAS microscopic visual analogue scale
• the best scars typically narrow scars with thick and randomly organised collagen fibres that have normal spacing between fibres, similar to the surrounding normal dermis
• bad scars typically wide scars with thin densely packed parallel collagen fibres
• the marks were measured from the left hand side to provide the final value for the scar assessment in centimetres (to 1 decimal place).
• Figures 4, 5 and 6 show representative macroscopic images of treated and control treated scars. Scars resulting from wounds treated with therapeutically effective amounts of WNT5A are considerably more difficult to detect than the scars produced on healing of untreated and control treated wounds.
• Figure 6 shows representative microscopic images from histological slides of scars produced on healing of WNT5A treated and untreated wounds. These show that the deposition of extracellular matrix molecules, such as collagen, found in WNT5A treated scars more closely approximates the arrangement in unwounded skin than does the extracellular matrix in untreated scars. This difference (i.e. this increased similarity to unwounded skin) is evident with reference to both the quantity of collagen present and the orientation of said collagen.
• Recombinant mouse WNT5A was purchased from R&D Systems (Catalogue number #645-WN/CF; Batch No: MCRl 36031.
• each injection of the O.Olng/lOO ⁇ l solution provided 0.2fmoles of WNT5A; each injection of the O.lng/lOO ⁇ l solution provided 2fmoles of WNT5A; each injection of the 0.5ng/100 ⁇ l solution provided O.Olpmoles of WNT5A; each injection of the lng/lOO ⁇ l solution provided 0.02pmoles of WNT5A; each injection of the lOng/lOO ⁇ l solution provided 0.22pmoles of WNT5A; each injection of the lOOng/lOO ⁇ l solution provided 2.2pmoles of WNT5A; each injection of the 500ng/100 ⁇ l solution provided l lpmoles of WNT5A; each injection of the 750ng/100 ⁇ l solution provided 16.5pmoles of WNT5A, and each injection of the lOOOng/lOO ⁇ l solution provided 22pmoles of WNT5A.
• the best scars (typically of small width with colour, height and contour like normal skin) were scored towards the normal skin end of the scale (the left hand side of the VAS line) and bad scars (typically large width, raised with uneven contours and whiter colour) were scored towards the bad scar end of the scale (the right hand side of the VAS line).
• the marks were measured from the left hand side to provide the final value for the scar assessment in centimetres (to 1 decimal place).
• FIG. 7 shows representative macroscopic images of treated and control treated scars. Scars resulting from wounds treated with therapeutically effective amounts of WNT5 A are considerably more difficult to detect than the scars produced on healing of control treated wounds.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Neurology (AREA)
• Biomedical Technology (AREA)
• Neurosurgery (AREA)
• Immunology (AREA)
• Gastroenterology & Hepatology (AREA)
• Heart & Thoracic Surgery (AREA)
• Marine Sciences & Fisheries (AREA)
• Cardiology (AREA)
• Epidemiology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Dermatology (AREA)
• Urology & Nephrology (AREA)
• Zoology (AREA)
• Ophthalmology & Optometry (AREA)
• Vascular Medicine (AREA)
• Pulmonology (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Rheumatology (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (7)

Applications Claiming Priority (2)

Publications (2)

Family

ID=36888398

Family Applications (1)

Country Status (11)

Cited By (4)

Families Citing this family (1)

Family Cites Families (8)

• 2006
  • 2006-06-30 GB GBGB0613031.4A patent/GB0613031D0/en not_active Ceased
• 2007
  • 2007-06-29 AU AU2007263593A patent/AU2007263593A1/en not_active Abandoned
  • 2007-06-29 EP EP07766148A patent/EP2046364A2/en not_active Withdrawn
  • 2007-06-29 MX MX2008016520A patent/MX2008016520A/es not_active Application Discontinuation
  • 2007-06-29 BR BRPI0713807-5A patent/BRPI0713807A2/pt not_active IP Right Cessation
  • 2007-06-29 ZA ZA200900708A patent/ZA200900708B/xx unknown
  • 2007-06-29 JP JP2009517409A patent/JP2009542609A/ja active Pending
  • 2007-06-29 CN CNA2007800318493A patent/CN101511383A/zh active Pending
  • 2007-06-29 US US12/306,501 patent/US20100137201A1/en not_active Abandoned
  • 2007-06-29 WO PCT/GB2007/002445 patent/WO2008001113A2/en not_active Ceased
  • 2007-06-29 CA CA002656965A patent/CA2656965A1/en not_active Abandoned

Also Published As

Similar Documents

Legal Events