Monday, October 20, 2008

Drug news: Argentis update

Meanwhile, Argentis is trucking right along with its hormonal treatments, hoping to get their Phase II clinical trial complete next year. (Don't get too excited yet... target market entry date is 2013. But some of you might be interested in participating in their Phase III trials when those get going, and that's probably just a year and a half off.

Momentum revs up for arGentis
Pharmaceutical firm in fast lane for clinical trials

arGentis Pharmaceuticals LLC is gaining momentum to get its first two therapies to the marketplace with a $10 million-$12 million capital campaign, new paths for clinical trials and a renowned business accelerator firm to help it find a drug development partner.

The Memphis pharmaceutical company is now negotiating with a clinical research organization to begin a Phase II trial of its dry eye therapy. That trial would take six weeks and company officials are hoping to conclude it in 2009. It would be followed by a lengthier Phase III trial. The therapy is projected to hit the market in 2013.

Drug news: Alcon's latest

Finally!!! It's about time we saw some Alcon dollars in the dry eye drug research world.

First, we've got cilomilast, which I've never even heard of in this context. Alcon are licensing it from GlaxoSmithKline for ophthalmic indications.

Then, we've got a closer relationship with Origenis:

Alcon expanded its existing drug research alliance with Origenis with a focus on the discovery and development of the small molecules that might one day have a role in the treatment of eye diseases.

Here's the whole article if you're interested:

Alcon Pads Eye-Disease Pipeline through Deals with GSK and Origenis

Newsblurb: Dry eyes in Ireland

First we had a big wave of dry eye publicity in the US where it seemed every slow news day had some sort of minimally educational article about dry eye and how to treat it, or at least how to line the pockets of a pharmaceutical company. Now we're seeing articles now and then in Europe and Asia on a regular basis. Here's one example:

Treat your eyes - take a screen break

eatment in eye clinics as a result of working on computers for long stretches.

Researchers at the University of Ulster showed one of the most common complaints is dry eye, which can affect large numbers of people but particularly those who work at computers indoors, in air-conditioned environments.

Johnny Moore, consultant ophthalmic surgeon, advises people to pay attention to the positioning of the computer and also to check out the humidity within the workplace or office.

"It is important that the user's seat and PC screen are adjusted to the correct height," he says. Other points to note include:

- Make the screen a bit duller as it makes it easier to read.

- People blink at least half as much as they normally do when looking at computer screen. The advice is to remember to blink and every now and then close your eyes for a few seconds.

- Every 10 minutes fix on an object 10 feet away for 10 seconds.

- Instead of reading long reams of text on the computer it may be better to print it off rather than having to concentrate for a long time on the screen.

- When you're working at your computer screen, stop every hour and take a two-minute break.

During this time, lie back in your chair and close your eyes. This will help to moisten and re-lubricate your eyes so they feel less dry and irritated.

Other advice is keep well hydrated in the modern, air-conditioned environment.

Researchers at the University of Ulster are currently undertaking a phase three clinical trial for a new drug for dry-eye treatment. Ulster is one of 30 centres across Europe involved in the research.

I wonder if Dr. Moore has any suggestions when his patients confirm that the humidity in their office has dropped into single digits....

Abstract: Vitamin A vs. Restasis for dry eye

...And it's a tie!


Both Vitamin A and Restasis appear to have improved everything EXCEPT symptoms. (Oops, I take that back, sounds like staining didn't improve either.)

Am J Ophthalmol. 2008 Oct 8.
A Comparison of Vitamin A and Cyclosporine A 0.05% Eye Drops for Treatment of Dry Eye Syndrome.
Kim EC, Choi JS, Joo CK.

PURPOSE: To compare the efficacy of vitamin A (retinyl palmitate) and cyclosporine A 0.05% eye drops in treating patients with dry eye disease. DESIGN: Prospective, randomized, controlled, parallel group study. METHODS: A total of 150 patients with defined dry eye disease participated (50 in each treatment group). In three identical clinical trials, patients were treated twice daily with cyclosporine A 0.05%, four times daily with retinyl palmitate 0.05%, or with no eye drops. Adjunctive treatment with preservative-free artificial tears was undertaken four times daily in all groups. Corneal fluorescein staining results, Schirmer tear test (without anesthesia) results, tear film break-up time (BUT), dry eye symptom score, and impression cytologic analysis results were obtained before treatment and at the first, second, and third months after initiation of treatment. RESULTS: Both vitamin A eye drops and topical cyclosporine A 0.05% treatments led to significant improvement in blurred vision, tear film BUT, Schirmer I score results, and impression cytologic findings in patients with dry eye syndrome (P < .05). CONCLUSIONS: Both vitamin A eye drops and topical cyclosporine A 0.05% treatments are effective for the treatment of dry eye disorder.

Abstract: Improving corneal topography on a dry eye

This study discusses a method for improving corneal topography accuracy when the tear film is too unstable to get a reliable result otherwise. This sounds like something that would be particularly useful for refractive surgery patients who have ablation irregularities and dry eye. The authors also mention this technique may later be useful in examining the tear film itself.

Estimating corneal surface topography in videokeratoscopy in the presence of strong signal interference
IEEE Trans Biomed Eng. 2008 Oct;55(10):2381-7. Links.
Alonso-Caneiro D, Iskander DR, Collins MJ.

Videokeratoscopy techniques rely on a number of factors in order to achieve accurate estimates of corneal surface topography. Good tear film quality, minimal reflections from eyelashes, and minimal eye movements are essential for corneal topography estimates to be reliable. However, in practice, these ideal conditions may not always be fulfilled, especially in cases of subjects diagnosed with dry eye syndrome, having narrow palpebral apertures, long eyelashes, or nystagmus (uncontrolled eye movements). Such nonoptimal conditions of image acquisition result in poorer estimates of corneal topography. The aim of this paper was to devise a technique that would provide more accurate estimation of corneal topography in such situations and particularly when the source of signal interference is strong. This was achieved by developing a set of algorithms that extract the interference from the acquired raw videokeratoscopic image and filter the topography according to the interference location. The experiments carried out with test surfaces and real corneas showed that this new technique leads to a significant improvement in the topography estimator. Additionally, it is an interference indication procedure that, in the future, could be used for the purpose of tear film quality estimation.

Abstract: Dry eye and cataract surgery

Good points... enough that I'll forgive the poor translation even.

[Not to ignore the dry eye of cataract patients after surgery]
Zhonghua Yan Ke Za Zhi. 2008 Apr;44(4):291-2.

Sun XG, Shi YY, Zhang C.

Dry eye syndrome following cataract surgery was concerned about recently. Two kinds of dry eye were clinically observed after cataract surgery, early dry eye and chronic dry eye. Most cases of early dry eye, who usually had the normal lacrimal secretion before surgery, were reversible and involved in some of factors associated with surgery and post-surgery medication. But most cases of chronic dry eye, who have abnormal lacrimal secretion or "borderline state" of lacrimal secretion test before surgery, may suffer from the ocular surface diseases related to irreversible dry eye disease. It is significantly important for maintaining of the ocular surface stability and recovery of vision acuity after cataract surgery to do early diagnose and promptly manage the dry eye syndrome.

Abstract: More on contact lenses

Companion study to the previous, examining more signs in contact lens wear.

Mucins and ocular signs in symptomatic and asymptomatic contact lens wear.
Optom Vis Sci. 2008 Oct;85(10):E930-8.

Berry M, Pult H, Purslow C, Murphy PJ.
University of Bristol, Academic Unit of Ophthalmology, Bristol, United Kingdom.

PURPOSE: Lid wiper epitheliopathy (LWE) and lid parallel conjunctival folds (LIPCOF) are related to dry eye symptoms in contact lens wearers. Both clinical signs are assumed to be related to mechanical forces during blinking. As the mucus layer is a protector of the ocular surface tissue, this study investigates whether any alterations of mucins are detectable comparing symptomatic and asymptomatic soft contact lens wearers.

METHODS: Comfort was evaluated using the Contact Lens Dry Eye Questionnaire. Corneal staining, LWE, and LIPCOF were assessed in the right eyes of 50 (19 men, 31 women; mean age, 32.1 +/- 11.4 years) experienced lens wearers. The tear film was sampled using Schirmer strips pressed onto the temporal conjunctiva and from harvested contact lenses. Mucins were assessed in dot-blots and Western blots after electrophoresis on 1% agarose or 4 to 12% NuPAGE Gels. Non-parametric analyses were used to study differences between groups and correlations between objective tests, mucins, and symptoms.

RESULTS: Thirty-one subjects were classified asymptomatic and 19 symptomatic by the questionnaire. LWE and LIPCOF were significantly increased in the symptomatic group (p < 0.035). MUC5AC reactivity was significantly decreased in symptomatics (p = 0.050). MUC4 was correlated to temporal LIPCOF and LWE, (r = -0.47 and -0.46; p < 0.01). MUC16 and MUC5AC correlated with corneal staining (0.36 < r < 0.53; p < 0.04).

CONCLUSIONS: Symptomatic contact lens wearers exhibit significantly more LWE and LIPCOF, and decreased MUC5AC reactivity. LWE and LIPCOF are significantly correlated; this may reflect their common frictional origin. Increased friction might follow from insufficient mucins, or an altered composition of the resident mucins at the ocular surface. In this study, we show that decreased mucin production is associated with the severity of LWE and LIPCOF.

Abstract: Clinical tests for successful contact lens wear

Rather an interesting one on attempts to quantify what makes for comfortable contact lens wear.

Clinical tests for successful contact lens wear: relationship and predictive potential.
Optom Vis Sci. 2008 Oct;85(10):E924-9.
Pult H, Purslow C, Berry M, Murphy PJ.

PURPOSE: Although comfort is important for contact lens wearers, common clinical tests can fail to predict patients' symptoms. Lid wiper epitheliopathy (LWE) and lid parallel conjunctival folds (LIPCOF) are related to dry eye symptoms in lens wearers. This study investigates the predictive value of LWE and LIPCOF as objective measures of discomfort, and their relation to the ocular surface in soft contact lens wearers.

METHODS: Subjects were classified as symptomatic or asymptomatic, using the Contact Lens Dry Eye Questionnaire (CLDEQ). Pre-lens tear break-up time (PLBUT), limbal and bulbar hyperaemia, corneal staining, LWE and LIPCOF were assessed in the right eyes of 61 (23 M, 38 F; mean age 32.1 years; range = 18 to 55) experienced contact lens wearers. Differences between groups, and relationships between LWE, LIPCOF (nasal, temporal and sum) and objective signs were examined using non-parametric analyses. The positive and negative predictive values for symptoms of each objective measure were calculated.

RESULTS: Thirty eight subjects were classified as asymptomatic, 23 symptomatic. LWE and LIPCOF severity scores were significantly increased in symptomatic patients (U-test, p < 0.03), while no significant differences were found between groups for PLBUT, corneal staining or hyperaemia (0.29 < p < 0.88). Significant positive correlations were found between LWE and LIPCOF scores (temporal r = 0.67, p < 0.001; nasal r = 0.39, p < 0.001), and between LWE and hyperaemia (bulbar, r = 0.28, p < 0.001; limbal r = 0.36, p < 0.001). Age and gender were different in the two groups (p < 0.05). The predictive value of temporal LIPCOF was positive = 56.9%, negative = 77.1% with a cutoff value of > or =2 (PPV/NPV/cutoff value), of nasal LIPCOF 70.7%/75.0%/> or =1, of LIPCOF Sum 79.8%/86.5%/> or =2, and of LWE 53.1%/81.1%/> or =1.

CONCLUSIONS: Contact lens wearers with dryness symptoms exhibit significantly more LWE and LIPCOF, but not increased corneal staining, bulbar hyperaemia or decreased PLBUT. LWE and LIPCOF are significantly correlated: this may reflect their common frictional origin. LIPCOF Sum severity scores appear to be most predictive for symptoms.

Abstract: Auto-immune dry eye

Decreased expression of antioxidant enzymes in the conjunctival epithelium of dry eye (Sjögren's syndrome) and its possible contribution to the development of ocular surface oxidative injuries.
Histol Histopathol. 2008 Dec;23(12):1477-83.
Cejková J, Ardan T, Simonová Z, Cejka C, Malec J, Dotrelová D, Brunová B.

Previous studies have described elevated lipid peroxidase, myeloperoxidase and xanthine oxidoreductase/xanthine oxidase levels on the ocular surface of patients suffering from autoimmune dry eye (Sjögren's syndrome, SS). Reactive oxygen species generated by various enzymatic systems may be dangerous to the eye if they are not sufficiently cleaved by antioxidants. Because antioxidants have not been investigated in dry eye, the aim of this study was to examine the expression of antioxidant enzymes that cleave reactive oxygen species and play a key role in antioxidant protection. Conjunctival epithelial cells of dry eye (SS) patients were obtained by the method of impression cytology using Millicell membranes. Normal eyes served as controls. In the conjunctival epithelium superoxide dismutase, catalase and glutathione peroxidase were examined immunohistochemically. The enzyme expression levels were determined by image analysis and statistical evaluation. In contrast to normal eyes, where antioxidant enzymes were highly expressed in the conjunctival epithelium, in dry eye their expression was much less pronounced in correlation with the increasing severity of dry eye symptoms. Our study suggests that the decreased expression of antioxidant enzymes in dry eye disease (SS) contributes to the development of anterior eye surface oxidative injuries.

Abstract: The Aging Lacrimal Gland

The Aging Lacrimal Gland: Changes in Structure and Function.
Ocul Surf. 2008 Oct;6(4):162-174.
Rocha EM, Alves M, Rios JD, Dartt DA.

ABSTRACT The afferent nerves of the cornea and conjunctiva, efferent nerves of the lacrimal gland, and the lacrimal gland are a functional unit that works cooperatively to produce the aqueous component of tears. A decrease in the lacrimal gland secretory function can lead to dry eye disease. Because aging is a risk factor for dry eye disease, study of the changes in the function of the lacrimal gland functional unit with age is important for developing treatments to prevent dry eye disease. No one mechanism is known to induce the changes that occur with aging, although multiple different mechanisms have been associated with aging. These fall into two theoretical categories: programmed theories of aging (immunological, genetic, apoptotic, and neuroendocrine) and error theories of aging (protein alteration, somatic mutation, etc). Lacrimal glands undergo structural and functional alteration with increasing age. In mouse models of aging, it has been shown that neural stimulation of protein secretion is an early target of aging, accompanied by an increase in mast cells and lipofuscin accumulation. Hyperglycemia and increased lymphocytic infiltration can contribute to this loss of function at older ages. These findings suggest that an increase in oxidative stress may play a role in the loss of lacrimal gland function with age. For the afferent and efferent neural components of the lacrimal gland functional unit, immune or inflammatory mediated decrease in nerve function could contribute to loss of lacrimal gland secretion with age. More research in this area is critically needed.

Abstract: Epithelial-immune cell interaction in dry eye

Should be an interesting read for the docs that can access the full article....

Epithelial-immune cell interaction in dry eye.
Cornea. 2008 Sep;27 Suppl 1:S9-11.
Pflugfelder SC, de Paiva CS, Li DQ, Stern ME.

Dry eye is a potent stimulus of both innate and adaptive immune systems. At the nexus of the dry eye inflammatory/immune response is the dynamic interplay between the ocular surface epithelia and the bone marrow-derived immune cells. On the one hand, ocular surface epithelial cells play a key initiating role in this inflammatory reaction. On the other hand, they are targets of cytokines produced by activated T cells that are recruited to the ocular surface in response to dry eye. This interaction between epithelial and immune cells in dry eye will be thoroughly reviewed.

Abstract: LASIK and the ocular surface

Nice succinct summary of the major ocular surface complications LASIK can present. Note in particular the reference to RCE happening to people who already had a poorly adhering epithelium. This is one of the reasons that if you're going to get laser surgery, you need to be evaluated really, really thoroughly by a specialist first... Mild ABMD is not obvious, and I know plenty of people who did not have it diagnosed before LASIK... and in a few cases, the first thing that caused them to learn about it was when their epithelium sloughed off after surgery. (By the way, that hurts. A lot.)

LASIK and the ocular surface.
Cornea. 2008 Sep;27 Suppl 1:S70-6.
Toda I.

Wound healing after LASIK sometimes compromises homeostasis of the ocular surface. Diffuse lamellar keratitis is a post-LASIK inflammatory condition in the interface that appears during the first week after LASIK. The etiology of diffuse lamellar keratitis is unknown, but the association with allergic reaction to detergent, bacteria, and other chemicals is suspected. The condition is mostly self-limiting. Topical and/or oral corticosteroids may be effective against stage 2 disease, whereas flap lift and irrigation might be required in stage 3. Epithelial ingrowth occurs in about 1% of LASIK eyes. Although most cases heal spontaneously, some require surgical removal. There are 2 known mechanisms for epithelial ingrowth: epithelial invasion and epithelial implantation. Epithelial invasion grows in 2 distinct ways--outside invasion and flap epithelial invasion. The latter type is often seen after enhancement and may be treatment resistant. Patients with compromised attachment of corneal epithelium before LASIK may develop recurrent corneal erosion, which sometimes requires phototherapeutic keratectomy. Subepithelial opacity after viral infection, even long after infection, often recurs after LASIK and affects refraction and visual acuity. Topical corticosteroid may be effective to prevent recurrence. Dry eye is a common complication after LASIK. Although post-LASIK dry eye is usually temporary, some patients complain of severe symptoms that may negatively influence their satisfaction with the outcome. For example, functional visual acuity significantly decreases after LASIK. The possible mechanisms for post-LASIK dry eye may be associated with loss of neurotrophic effect, damage of goblet cells, and altered corneal shape.

Some of you whose lives have been turned upside down for a couple of years by severe post LASIK dry eye might get a giggle out of this understatement from the abstract:

Although post-LASIK dry eye is usually temporary, some patients complain of severe symptoms that may negatively influence their satisfaction with the outcome.

For the laypeople reading this, don't forget "usually" can mean anywhere between 51% on up (and doctors, before you're tempted to tell me I'm overdramatizing things, go back and read the published studies that showed between 15 and 36% of patients having unresolved dry eye 6 months after surgery).

And any doctor that is surprised 24/7 pain can make you dissatisfied with an elective surgery, please raise your hand (grin).


On Saturday, March 7, 2009 the Sjogrens Syndrome Foundation will be hosting a one-day dry eye conference at the Marriott in Long Beach, California. There will be several doctors speaking, including SSF board chairman Gary Foulks MD, and there will be several companies exhibiting.

All dry eye topics will be covered (not just Sjogrens) and all dry eye patients are welcome to attend!

We don't have anything settled yet but... we'll definitely be having some kind of DryEyeZone social get-together that weekend, Friday or Saturday evening (or both).

More details will be posted here and on DryEyeTalk after the program is finalized. I'll also have brochures available.

Abstract: Signs vs. symptoms in Sjogrens patients

Hmph. I thought I had already reported on this but can't find it on the blog so I guess I didn't.

Basically just tells us... as we know... that the correlation between dry eye signs and symptoms is poor even for Sjogrens Syndrome patients, and suggests that reduced corneal sensitivity is part of the explanation.

[Correlation between signals and symptoms of dry eye in Sjögren's syndrome patients]
Arq Bras Oftalmol. 2008 Jul-Aug;71(4):547-52.
[Article in Portuguese]

Barboza MN, Barboza GN, de Melo GM, Sato E, Dantas MC, Dantas PE, Felberg S.

PURPOSE: To study the correlation between the signals and symptoms of dry eye in Sjögren's syndrome patients.

METHODS: We formed the case group with 17 Sjögren's syndrome patients and the control group with 25 normal patients. For evaluation of the symptoms the "Ocular Surface Disease Index (OSDI)" questionnaire was applied to both groups and, after that, all the individuals were submitted to the ocular tests: Schirmer I and II, coloration of the ocular surface with rose bengal, pachymetry and esthesiometry. Spearman's correlation test was used to analyze the correlations between signals and symptoms and Student's t test for independent samples was used for comparison of the averages of the values found by the "Ocular Surface Disease Index (OSDI)" questionnaire and the ocular tests between the patients of the groups.

RESULTS: This study had evidenced a weak correlation between "Ocular Surface Disease Index (OSDI)" symptoms and ocular tests, which it indicates that not all the patients who presented exuberant symptoms, showed proportionally modified tests. The cornea sensitivity of the case group was reduced when compared with that of the control group. All the studied parameters in the case group presented significant differences (p<0.05) when compared with the control group.

CONCLUSION: There was a weak correlation between Sjögren's syndrome patients' ocular symptoms and signals that indicate the severity of the illness. The variation of cornea sensitivity found in the Sjögren's syndrome patient group may be one of the responsible factors for this weak correlation. All the studied parameters were significantly modified in the Sjögren's syndrome patients group when compared with those found in the control group.

Abstract: Autologous serum (again)

While talking recently with a lady with severe post PRK dry eye who had recently sought (yet) another opinion from a well reputed corneal specialist, I was rather disgusted to hear that the doctor stated flatly that she does not ever use autologous serum because "it doesn't work". Hm. News to me. There has been a plethora of studies about it in the last couple of years - clearly it's helping at least enough people to fill a lot of studies and it does not deserve the big brush-off from ophthalmologists, especially if they have been unable to resolve their patients' symptoms in other ways.

Incidentally, the same doctor professed not to believe that PRK can cause dry eye or that LASIK can cause persistent dry eye. What is wrong with these people? Have they drunk too much pharmaceutical kool-aid, or don't they read their own peers' published studies at least once in awhile?

Autologous serum eye drops for the treatment of dry eye diseases.
Cornea. 2008 Sep;27 Suppl 1:S25-30.

Kojima T, Higuchi A, Goto E, Matsumoto Y, Dogru M, Tsubota K.
Department of Ophthalmology, Social Insurance Chukyo Hospital, Nagoya, Japan.

Conventional treatment of dry eye mainly consists of the use of preservative-free artificial eye drops and punctal occlusion. None of the commercially available artificial tear preparations include essential tear components such as epidermal growth factor, hepatocyte growth factor, fibronectin, neurotrophic growth factor, and vitamin A-all of which have been shown to play important roles in the maintenance of a healthy ocular surface epithelial milieu. We reported previously that autologous serum (AS) eye drops contain these essential factors and that AS eye drops are beneficial in the treatment of ocular surface diseases such as persistent epithelial defects, superior limbic keratoconjunctivitis, keratoconjunctivitis sicca, and neurotrophic keratopathy. However, there is some controversy regarding the efficacy of AS treatment. We demonstrated that this modality is more effective than artificial tears in a randomized control study. In in vivo and in vitro experiments, AS eye drops showed marked suppression of apoptosis in the conjunctival and corneal epithelium. Albumin, the major protein in serum, improved ocular surface damage in vivo and rescued apoptosis after serum deprivation in vitro. The biological background of AS eye drops and previous clinical studies of these medications for the treatment of dry eye are discussed.

Abstract: Tear film biomarkers

Compositional Profiling and Biomarker Identification of the Tear Film.
Ocul Surf. 2008 Oct;6(4):175-185.
Jacob JT, Ham B.

ABSTRACT Identification of tear film proteins and lipids is important for the elucidation of contact lens incompatibilities, tear film instabilities, dry eye syndromes, and other eye diseases. Compositional analysis of the tear film has been hampered in the past by the complex nature of the fluid and small sample size. Previously, all analytical methods required pooling of tear samples and molecular manipulation for detection of proteins and lipids, all of which skewed the resultant data. With the advent of nanoscale detection and analysis methods, it has become possible to identify specific tear components. This paper reviews the recent advances in tear sampling, proteomics, and lipidomics. Compositional profiling techniques, such as multi-dimensional electrophoresis, high performance liquid chromatography, and mass spectrometry, are assessed. Application of these techniques to identify potential biomarkers for specific tear disease conditions, such as blepharitis and dry eye, are evaluated.

I finally strained the budget and renewed my subscription to The Ocular Surface.... nice to be able to read the whole thing agin. This article is an in-depth review of advances in understanding tear film composition better.

For those of you who wonder why there isn't a "cure" for dry eye yet... thought you might be interested in this statement from the article's introduction, showing just how far we have to go on understanding the tear film itself, lot alone how to fix it:

...We currently have very little definitive information regarding which specific elements change in response to glandular disease or environmental issues. Nor do we know the concentrations of these elements that can induce physiological changes in the tear film. Although the signs and symptoms of tear film instability have been fairly well characterized, the specific etiology and physiological changes responsible for that instability are not well known.

Abstract: More on Lacritin

Some of the DEZ old-timers will remember when we first came across Lacritin. Here's a newly released study about it. I didn't realize that it could have implications for blepharitis too.

Exp Eye Res. 2008 Sep 18.
Lacritin and other new proteins of the lacrimal functional unit.
McKown RL, Wang N, Raab RW, Karnati R, Zhang Y, Williams PB, Laurie GW.

The lacrimal functional unit (LFU) is defined by the 2007 International Dry Eye WorkShop as 'an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva and meibomian glands) and lids, and the sensory and motor nerves that connect them'. The LFU maintains a healthy ocular surface primarily through a properly functioning tear film that provides protection, lubrication, and an environment for corneal epithelial cell renewal. LFU cells express thousands of proteins. Over 200 new LFU proteins have been discovered in the last decade. Lacritin is a new LFU-specific growth factor in human tears that flows through ducts to target corneal epithelial cells on the ocular surface. When applied topically in rabbits, lacritin appears to increase the volume of basal tear secretion. Lacritin is one of only a handful of tear proteins preliminarily reported to be downregulated in blepharitis and in two dry eye syndromes. Computational analysis predicts an ordered C-terminal domain that binds the corneal epithelial cell surface proteoglycan syndecan-1 (SDC1) and is required for lacritin's low nanomolar mitogenic activity. The lacritin-binding site on the N-terminus of SDC1 is exposed by heparanase. Heparanase is constitutively expressed by the corneal epithelium and appears to be a normal constituent of tears. Binding triggers rapid signaling to downstream NFAT and mTOR. A wealth of other new proteins, originally designated as hypothetical when first identified by genomic sequencing, are expressed by the human LFU including: ALS2CL, ARHGEF19, KIAA1109, PLXNA1, POLG, WIPI1 and ZMIZ2. Their demonstrated or implied roles in human genetic disease or basic cellular functions are fuel for new investigation. Addressing topical areas in ocular surface physiology with new LFU proteins may reveal interesting new biological mechanisms and help get to the heart of ocular surface dysfunction.

I was thinking this was the first published study on lacritin in ocular surface research but I found one other on Medline that I must have missed last year:

Establishment of an appropriate animal model for lacritin studies: cloning and characterization of lacritin in monkey eyes.