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  Pharmaceutical Patents  

 

Title:  Investigation of mucosa dryness conditions
United States Patent: 
8,080,428
Issued: 
December 20, 2011

Inventors:
 Beuerman; Roger (Singapore, SG), Zhou; Lei (Singapore, SG), Liu; Shouping (Singapore, SG), Yang; He (Singapore, SG), Tan; Donald (Singapore, SG)
Assignee:
  Singapore Health Services Pte Ltd. (Singapore, SG)
Agency for Science, Technology and Research (Singapore, SG)

Appl. No.:
 12/298,829
Filed:
 April 26, 2007
PCT Filed:
 April 26, 2007
PCT No.:
 PCT/SG2007/000118
371(c)(1),(2),(4) Date:
 October 28, 2008
PCT Pub. No.:
 WO2007/126391
PCT Pub. Date:
 November 08, 2007


 

George Washington University's Healthcare MBA


Abstract

The present invention relates to diagnosis and/or treatment of medical conditions. The present invention relates to new method of diagnosing dry mucosa condition in a subject. The condition may be dry eye. The present invention also provides a method to monitor the efficacy of a treatment of a dry mucosa condition, a method of treating a dry mucosa condition and/or a diagnostic kit for a dry mucosa condition.

Description of the Invention

FIELD OF THE INVENTION

The present invention relates to medical conditions. In particular, the present invention relates to mucosa dryness conditions.

BACKGROUND OF THE INVENTION

Sjogren Syndrome is an autoimmune inflammatory disease characterized by a particular form of dry mouth and dry eyes. It affects the lacrimal gland's ability to secrete tears and results in dry eye, salivary gland dysfunction, causing dry mouth and dryness in other mucous membranes such as the bronchial epithelium, the vagina and other mucosa.

This loss of tear and saliva fluids may result in characteristic changes in the eyes (called aqueous tear deficiency or keratoconjunctivitis sicca) and in the mouth with deterioration of the teeth, increased oral infection, difficulty in swallowing, and painful mouth. However, dry mucosa may also be due to other causes classified under the non-Sjogren Syndrome. The causes may be due to use of certain types of drugs, inflammation or infection, or hypothyroidism. Dry mucosa conditions due to any cause can affect both humans and animals such as mammals.

For the eyes, the lacrimal gland located in the orbit of the eye continuously secretes small amounts of tear fluid that are released onto the surface of the eye through very small ducts. Dry eye syndrome can be defined as a loss of tear fluid with accompanying abnormalities of the tear film. There are few objective signs of dry eye and importantly, discomfort which varies on an individual basis is the aspect that is most noticed by patients and which motivates them to seek help [1]. For severe cases, ocular surface damage and a loss of vision is not uncommon. Dry eye syndrome affects millions of people and its prevalence is estimated to be as high as 11.about.22% of the general population with the prevalence in Asia greater than in the West [1]. It is more common in people over 55 years of age and in females; however, in Asia, dry eye is a factor in those over 45 [2]. The prevalence is also significantly higher in visual display terminal users and contact lens wearers.

The causes for dry eye syndrome are diverse; however, fundamentally it is due to a loss of fluid over the ocular surface and particularly the cornea. The cornea is the most important optical element of the eye and dry eye decreases good vision as well as the quality of life of the patient. The fluid layer over the ocular surface, called the tear layer, is some microns thick but has layers as follows: 1-outermost lipid layer, 2-middle aqueous layer and 3-inner mucin layer. Usually it can be classified into two major categories: tear secretion deficiency and excessive tear evaporation. Dysfunction of the lipid layer of the tear film leads to excessive evaporation of tears. A mucin layer deficiency often caused by vitamin A deficiency; however, except for developing countries, it is rare.

For therapeutic development by pharmaceutical companies for dry eye, non-Sjogren's dry eye is the primary target as it comprises the majority of these patients. At present there is only one actual therapeutic drug on the market, Restasis.RTM. from Allergan.RTM.. The reasons for this paucity in drug development arise primarily from the lack of objective measures of dry eye and therapeutic efficacy.

Diagnosis of dry eye syndrome is typically based on subjective symptoms, Schirmer test (evaluating quantity of tear fluid), tear break-up time (evaluating quality of tear film) and other less common clinical tests including fluorescein staining, Rose Bengal staining, measuring tear meniscus height, impression cytology, and others. Studies show that correlation is poor between clinical tests and symptoms and even between different clinical tests [3, 4]. This also makes a difficult scenario for the evaluation of therapeutic agents [5].

As such, new and improved methods of determining and diagnosing dry mucosa conditions such as dry eye are welcome.

SUMMARY OF THE INVENTION

The present invention addresses the problems above, and in particular, provides methods for diagnosis and treatment of a medical condition. In general, the present invention provides new method to diagnose dry mucosa condition in a subject.

In one aspect, the present invention relates to a method of diagnosing a dry mucosa condition in a subject, the method comprising: providing a sample from the subject; and comparing expression of at least one biomarker in the sample, the at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein, prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein, and any of their derivative or fragment thereof with at least one reference value.

In another aspect, the present invention provides a method of determining the severity of the condition of dry mucosa in a subject, the method comprising: providing a sample from the subject; and comparing the relative expression of .alpha.-1-acid-glycoprotein, S100 A8, S100 A9, S100 A4, S100 A11, lactoferrin, lysozyme, and/or any of their derivative or fragment thereof in the sample with at least one reference value.

In another aspect, the present invention provides a method of monitoring efficacy of a treatment for a dry mucosa condition in a subject, the method comprising: providing a sample from the subject; and comparing expression of at least one biomarker in the sample, the at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein, prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein and any of their derivative or fragment thereof with at least one reference value.

In another aspect, the present invention provides a method of treating a dry mucosa condition in a subject, the method comprising: providing a sample from the subject; comparing expression of at least one biomarker in the sample, the at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein and prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein and any of their derivative or fragment thereof; and reducing the difference in expression of at least one biomarker in the group of biomarkers.

In the above aspects, the dry mucosa condition may be dry eye. The comparing may be with at least one reference value determined from at least one subject not exhibiting signs of, or experiencing symptoms of the dry mucosa condition, and/or the comparing may be with at least one reference value determined from a statistically significant number of subjects not exhibiting signs of, or experiencing symptoms of the dry mucosa condition. The sample may be a fluid. The expression of the biomarker may be reflected in, or measured by the abundance of the at least one biomarker. The comparing may be by mass spectrometry. The subject may be a human being or a mammal.

Under the method for treating a dry mucosa condition, the at least one biomarker may be .alpha.-1-acid-glycoprotein 1 and the reducing of the difference in expression comprises reducing inflammation in the subject. The at least one biomarker may be prolactin-inducible protein and the reducing of the difference in expression comprises increasing the expression of prolactin-inducible protein in the subject by the administration of prolactin and/or androgen. The at least one biomarker may be S100 A8 and S100 A9 and the reducing of the difference in expression comprises reducing the upregulation and/or complex formation, of S100 A8 and S100 A9 in the subject.

In another aspect, the present invention provides a panel of biomarkers for diagnosing the condition of dry eye, the panel comprising .alpha.-enolase, prolactin-inducible protein, .alpha.-1-acid-glycoprotein, S100 A8, S100 A9, S100 A4, S100 A11, lactoferrin, lysozyme, von Ebner's gland protein, proline-rich 4 protein, and/or a derivative or fragment thereof with at least one reference value. The panel may provide a more detailed profile of the condition, yielding both diagnostic as well as prognostic information, as compared to the results from only a few of the other biomarkers. The panel of biomarkers may be on a solid support or in a gel.

In another aspect, the present invention provides a diagnostic kit for diagnosing a dry mucosa condition comprising at least one chemical capable of reacting to at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein and prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein and a derivative or fragment thereof. The at least one chemical may be at least one antibody specific for any one of the biomarkers. The at least one chemical may be on a solid support or in a gel. The at least one biomarker may be .alpha.-enolase and the at least one chemical is 2-phosphoglycerate. The diagnostic kit may further comprise information pertaining to the use of the kit.

DETAILED DESCRIPTION

In one aspect, the present invention relates to a method of diagnosing a dry mucosa condition in a subject, the method comprising: providing a sample from the subject; and comparing expression of at least one biomarker in the sample, the at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein, prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein and any of their derivative or fragment thereof with at least one reference value. In another aspect, the present invention provides a method of determining the severity of the condition of dry mucosa in a subject, the method comprising: providing a sample from the subject; and comparing the relative expression of .alpha.-1-acid-glycoprotein, S100 A8, S100 A9, S100 A4, S100 A11, lactoferrin, lysozyme, and/or any of their derivative or fragment thereof in the sample and any of their derivative or fragment thereof in the sample with at least one reference value.

In another aspect, the present invention provides a method of monitoring efficacy of a treatment for a dry mucosa condition in a subject, the method comprising: providing a sample from the subject; and comparing expression of at least one biomarker in the sample, the at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein and prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein and any of their derivative or fragment thereof.

In another aspect, the present invention provides a method of treating a dry mucosa condition in a subject, the method comprising: providing a sample from the subject; comparing expression of at least one biomarker in the sample, the at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein and prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein and any of their derivative or fragment thereof; and reducing the difference in expression of at least one biomarker in the group of biomarkers.

In the above aspects, the dry mucosa condition may be dry eye. The comparing may be with at least one reference value determined from at least one subject not exhibiting signs of, or experiencing symptoms of the dry mucosa condition, and/or the comparing may be with at least one reference value determined from a statistically significant number of subjects not exhibiting signs of, or experiencing symptoms of the dry mucosa condition. The sample may be a fluid. The expression of the biomarker may be reflected in, or measured by the abundance of the at least one biomarker. The comparing may be by mass spectrometry. The subject may be a human being or a mammal.

Under the method for treating a dry mucosa condition, the at least one biomarker may be .alpha.-1-acid-glycoprotein 1 and the reducing of the difference in expression comprises reducing inflammation in the subject. The at least one biomarker may be prolactin-inducible protein and the reducing of the difference in expression comprises increasing the expression of prolactin-inducible protein in the subject by the administration of prolactin and/or androgen. The at least one biomarker may be S100 A8 and S100 A9 and the reducing of the difference in expression comprises reducing the upregulation and/or complex formation, of S100 A8 and S100 A9 in the subject.

In another aspect, the present invention provides a panel of biomarkers for diagnosing the condition of dry eye, the panel comprising .alpha.-enolase, prolactin-inducible protein, von Ebner's gland protein, proline-rich 4 protein, and a derivative or fragment thereof. The panel may provide a more detailed profile of the condition, yielding both diagnostic as well as prognostic information, as compared to the results from only a few of the other biomarkers. The panel of biomarkers may be on a solid support or in a gel.

In another aspect, the present invention provides a diagnostic kit for diagnosing a dry mucosa condition comprising at least one chemical capable of reacting to at least one biomarker selected from the group consisting of .alpha.-enolase, .alpha.-1-acid-glycoprotein and prolactin-inducible protein, S100 A8, S100 A9, S100 A4, S100 A11, von Ebner's gland protein, lactoferrin, lysozyme, proline-rich 4 protein and a derivative or fragment thereof. The at least one chemical may be at least one antibody specific for any one of the biomarkers. The at least one chemical may be on a solid support or in a gel. The at least one biomarker may be .alpha.-enolase and the at least one chemical is 2-phosphoglycerate. The diagnostic kit may further comprise information pertaining to the use of the kit.

Under the present invention, the detection, identification, and/or quantification at least one biomarker of a group of biomarkers associated with dry mucosa provides a basis for the diagnosis of a dry mucosa condition. Specifically, the detection, identification, and/or quantification at least one biomarker of a group of biomarkers in tear fluid of a subject provides the basis for diagnosing the condition of dry eyes due to any cause.

Any one or more biomarker of this group of biomarkers may be detected, identified, and/or quantified by one or more suitable methods. Any variation from a normal range of expression of these biomarkers indicates the condition of dry eye, whether or not the subject complains of the condition.

To measure the expression of one or more of these biomarkers, tear fluid is obtained from the subject and biomarkers are detected, identified, and/or quantified. Many methods are available in the art under the present invention such as immunological reactions (eg Enzyme-Linked Immunosorbent Assay) and other biochemical reactions such as enzymatic reactions. Such reactions may comprise detecting the biomarker by photometric means such as a colour change or a difference in absorbance or transmission of light at certain wavelengths.

Another suitable method for use is mass spectroscopy (MS), well known to a person skilled in the art. A modern MS system comprises ionization, detection and analysis means. For analysis of the sample, the system may compare the data obtained from the detection means with known standards to identify the components in the sample, or the system may compare different components within the same sample to derive the results.

Under the present invention, the quantitative proteomics method, iTRAQ technology [6] with 2 dimensional liquid chromatography and tandem mass spectroscopy in the nanoscale (nanoLC-nano-ESI-MS/MS), was combined with statistical analysis and used to detect, identify and quantify biomarkers in the tear fluid of patients diagnosed with dry eye syndrome with a loss of tear secretion. NanoLC-nano-ESI-MS/MS is well known in the art and was developed to separate complex protein mixtures which were previous inadequately performed using one- or two-dimensional polyacrylamide gel electrophoresis (1D or 2D PAGE) [20].

In order attain sufficient confidence in the use of detected biomarkers for the diagnosis of dry eye, stringent criteria are set for the analysis of the MS data followed by statistical analysis to provide indication of the severity of the condition.

Biological functions of the biomarkers under the present invention for the diagnosis of dry mucosa condition are as follows.

.alpha.-enolase: .alpha.-enolase (ae) is one of the key glycolytic enzymes that is expressed abundantly in many cells. However, more recently it was also found on the cell surface as a surface protein [7] in such cells as hematopoietic cells (neutrophils, B cells, T Cells, monocytes), epithelial cells, neuronal cells, etc. In addition to its innate glycolytic function, .alpha.-enolase has been recognized as a multifunctional protein. Very recent studies indicate that it may play an important role in several disease processes, for example, many autoimmune disorders, cancer, systemic fungal disease and dental diseases. However, this is the first report of the presence of .alpha.-enolase in tear fluid. .alpha.-1-acid glycoprotein 1: .alpha.1-acid glycoprotein 1 (AGP) is a heavily glycosylated protein (45%) with a molecular weight of 41-43 kDa [8]. It also belongs to the lipocalin family. It is associated with inflammatory responses. The synthesis is controlled by glucocorticoids, interleukin-1 and interleukin-6. Its anti-inflammatory effects were noted. AGP exhibits both pro- and anti-inflammatory effects. These dual immunomodulatory effects may indicate that AGP plays an important role in the regulation of immune response and inflammation. This is also the first report of detecting .alpha.1-acid glycoprotein 1 in tear fluid. S100 A8 and S100 A9: S100 A8 and A9 belong to S100 calcium-binding protein family. There is growing evidence to show that S100 A8, A9 and A12 form a new group of pro-inflammatory proteins [9]. In inflammatory diseases, the over-expression of both S100 A8 and S100 A9 are typically seen. They are secreted at sites of inflammation. The over-expression of only S100 A8 in dry eye tears has been previously reported [10]. These two proteins can form complexes which induces apoptosis when present in high concentrations. S100 A4: S100 A4 is a member of S100 calcium binding protein family. The best known role of S100 A4 is its ability to cause cell shape changes. More recently [11], it was shown that S100 A4 is capable of stimulating corneal neovascularization in vivo. S100 A4 also appears to take part in the homeostasis of growth, with apparent involvement in growth factor signal transduction and apoptotic cell death. There is considerable evidence that S100 A4 expression alters the adhesion properties of cells, possibly by remodelling the extra-cellular matrix and promoting a redeployment of adhesion-mediating macromolecules occurring in the extracellular matrix [12]. S100 A11: This is another member in S100 calcium binding protein family. S100 A11 seems to be involved in apoptosis [13]. Lactoferrin and lysozyme: These are well known, abundant human tear proteins. They both have anti-bacterial activity on the ocular surface. In previous studies, the down-regulation of these two tear proteins was observed in patients with dry eye [14, 10]. von Ebner's gland protein: von Ebner's gland protein, also called tear specific prealbumin (TSPA) or tear lipocalin [15], is one of the major tear proteins and acts as the principal lipid binding protein. It is regarded as general protection factor for the epithelial surface. Prolactin-inducible protein: Prolactin-inducible protein (PIP) is typically expressed in several exocrine tissues, such as the lacrimal, salivary, and sweat glands and may also be associated with breast cancer [16]. A very recent study showed that it is down-regulated in tears of blepharitis patients but this would be the first reported association with dry eye [17]. Proline-rich 4 protein:_It is also regarded as one of the abundant tear proteins recently [18, 10]. Proline-rich protein 4 is expressed abundantly in lacrimal gland where it is found in the acinar cells [19]. It may reflect the function of the acinar cells. It has been shown to be down-regulated in dry eye patients [10].

Once diagnosis of a dry mucosa condition such as dry eye is made using the method of the present invention, it will be possible to also use the method to monitor the efficacy of a treatment for the condition. A subject may be prescribed a course of treatment and monitored at intervals by periodic determination of the expression of one or more of the biomarkers of the present invention. The type and duration of treatment of such dry mucosa conditions and the interval and duration of monitoring of the efficacy of treatment will be known to a person skilled in the art such as a physician. The method of present invention may also be used to monitor the efficacy of a new treatment method in drug trials.

The present invention also provides a method to treat a dry mucosa condition by countering the causes of variation of one or more of the biomarkers of the present invention to return the expression of one or more of the biomarkers back to the normal range.

The present invention also provides a panel of biomarkers for the diagnosis and to profile a dry mucosa condition. While the expression of several biomarkers may be changed by the medical condition, the panel of biomarkers provides more specific and precise diagnosis of the condition. When the biomarkers on the panel are measured, the relative expression or abundance of the biomarkers on the panel to each other can indicate the severity of the condition.

The present invention also provides a diagnostic kit for the diagnosis of a dry mucosa condition such as dry eye. The kit comprises at least one chemical capable of reacting with one or more biomarkers such that the reaction may be detected. For example, the chemical may be an antibody that specifically binds to a biomarker. Alternatively, the chemical may be a substrate for the biomarker. These chemicals may be on a support such as a solid support or a gel. The diagnostic kit may give a qualitative and/or quantitative result that allows the medical condition to be diagnosed.

Having now generally described the invention, the same will be more readily understood through reference to the following examples which are provided by way of illustration, and are not intended to be limiting of the present invention.

EXAMPLES

Methods

Example 1

Patients

A total of 28 patients clinically diagnosed with dry eye syndrome and 20 control subjects with no other ocular diseases were recruited. Informed consent was obtained from all participating subjects and the whole procedure was approved by Institutional Review Board committee of Singapore Eye Research Institute (SERI) and also adhered to the tenets of the Declaration of Helsinki. Clinical examinations included subjective symptoms, Schirmer test (without anesthesia), tear break-up time (TBUT) test, and other general ophthalmic examinations such as visual acuity and lid margin and meibomian gland appraisal. Typical affective symptoms for dry eye include burning, itching and stinging, foreign body sensation, sense of dryness, blurring of vision, photophobia, pain and heavy or tired eyes. Patients were classified as having dry eye based on the Schirmer test, TBUT, and subjective symptoms.

Example 2

Collection and Tear Protein Elution

Tear fluids for all patients were collected using the Schirmer strip. For this test, a thin tear strip (of paper) is placed inside the lower eyelid for 5 mins without anesthesia. Tears collected were subsequently eluted off of the strip. The ability to do this was critical as the reduction in tears made it impractical to collect tears using the capillary method. After collection, Schirmer strips were immediately frozen at -80.degree. C. until analysis. The first 10 mm of Schirmer strip was cut into small pieces and soaked in 150 .mu.l of phosphate-buffered saline (PBS) for 3 hours to elute the tear proteins from the Schirmer strip. Total tear protein concentrations were then measured using a Micro BCA Protein Assay Kit (Pierce Biotechnology, Inc.) for each sample.

Example 3

Study Design and iTRAQ (Isobaric Tags for Relative and Absolute Quantification iTRAQ) Sample Preparation

Since iTRAQ technology allows labeling 4 samples simultaneously, 2 controls (C) and 2 dry eye samples (DE) were used in each set (a total of 14 sets). In these 14 sets, individual control samples were used in 9 sets and pooled control samples (one pooled from 5 controls and one pooled from 3 controls) were used in another 5 sets of experiments. 30 .mu.g from each sample was used for the iTRAQ experiments. The iTRAQ procedure was followed according to the protocol provided by Applied Biosystems (Foster City, Calif.). Here, 20 .mu.l of Dissolution Buffer (triethylammonium bicarbonate) and 1 .mu.l of Denaturant (2% SDS) from the iTRAQ reagent kit were added to the samples. Then 2 .mu.l of Reducing Reagent (tris-(2-carboxyethyl)phosphine) was then added and the samples incubated at 60.degree. C. for 1.5 h. In the next step 1 .mu.l of Cysteine Blocking Reagent (methyl methanethiosulfonate) was added and incubated at room temperature for 20 min. The samples were then digested at 37.degree. C. overnight with trypsin. iTRAQ reagents 114 and 115 were added to the control samples while iTRAQ reagents 116 and 117 were added to the dry eye samples. The samples were then incubated at room temperature for 3 h. The contents of each iTRAQ reagent labeled sample were combined and dried using a SpeedVac concentrator. For testing, 10 .mu.l of loading buffer (0.1% formic acid, 2% acetonitrile in water) was added to reconstitute the sample before performing the 2D nano-LC-nano-ESI-MS/MS analysis.
 

Claim 1 of 8 Claims

1. A method of diagnosing dry eye in a subject, the method comprising: (i) providing a tear fluid sample from said subject; (ii) measuring the expression of .alpha.-enolase in said sample by mass spectrometry; and (iii) comparing expression of .alpha.-enolase from said sample to a reference value from a statistically significant number of control subjects not exhibiting signs or experiencing symptoms of dry eye, wherein the subject is diagnosed with dry eye if a ratio of .alpha.-enolase from said sample to said reference value is greater than 1.70.
 

 

 

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