lacritin

[Alexandra]

maybe thats news. doesnt sound bad:

http://www.isat.jmu.edu/pdf/2007symposiumschedule.pdf

rebecca:no, sorry, dont know more about NGF....

[GordonLaurie]

lacritin update '07

Here is a short update on our lacritin studies over the past year.

The implications are very exciting, although the results may come across as technical.

We first asked how lacritin specifically targets cells. This is a fundamental question in new drug discovery. We found that lacritin binds 'syndecan-1' via a novel `off/on' switch mechanism. Syndecan-1 is a cell surface proteoglycan that covers the surfaces of corneal epithelial cells where it is anti-inflammatory. Proteoglycans are proteins with very long sugar chains. The sugar chains on syndecan-1 are mostly 'heparan sulfate'. Lacritin can bind syndecan-1 only if heparan sulfate chains are removed by `heparanase'. Thus heparanase regulates lacritin function. Heparanase is normally produced by corneal epithelial cells and is important for the health of these cells (often you hear of heparanase as inflammatory, but this is only heparanase produced by T-lymphocytes).

We believe that lacritin binding of corneal syndecan-1 via heparanase makes it possible to bind a 'signaling receptor' that leads to tearing. We are trying to identify this receptor. Lacritin also can promote cell growth if there are insufficient corneal epithelial cells. It also appears to protect these cells against inflammatory agents. Thus lacritin seems to be multifunctional.

Another component of new drug discovery is to study 'cell signaling'. In other words, we ask 'how does binding of syndecan-1 on the cell surface (with the help of heparanase) activate cells to produce tears?' Several years of work later, we have sketched out diverging G-alpha/PKCalpha/PLC/calcium/NFAT and G-alpha/PKCalpha/PLD/mTOR pathways. These pathways come across as very technical, but the involvement of 'NFAT' and 'mTOR' in cells is very exciting and gives us many ideas on how lacritin works. It gives us information for example on what might enhance the lacritin effect.

Two forms of lacritin have been identified that are likely inactive. If one or both of these forms are produced at the expense of 'good' lacritin, problems could occur. At ARVO a preliminary clinical study revealed that lacritin was substantially downregulated in contact lens-related dry eye. Over the next year we will be developing an assay to measure 'good' and 'bad' lacritin in normal and dry eye tears.

Several years ago, we formed a 'Lacritin Consortium' of collaborating labs within Virginia (in Biomedical Engineering and Ophthalmology at the University of Virginia; in Biotechnology at James Madison University, in Ocular Pharmacology at Eastern Virginia Medical School, at EyeRx) and outside (Walter Reed Ophthalmology). We meet several times a year. This group devotes much of the discussion towards applyng lacritin to dry eye. EyeRx did the first preclinical studies in rabbits that showed promising tearing effects of lacritin (reported in last year's posting). They recently received federal funding to expand these studies. Aims include the development of a form of lacritin that can be manufactured for dry eye use.

Our collaboration with Senju Pharmaceutical continues.

Much of our cell biological work will help the new EyeRx preclinical studies and Senju Pharmaceutical studies move forward more quickly. We believe it will also help scientists better understand the efficacy and mechanism of action of other dry eye drugs.

We have several interesting lacritin discoveries under study that I will report on later.

Below are two new lacritin patent applications and three new publications.

Lacritin-Syndecan Interactions, Patent pending, 2006.
Use of Lacritin in Promoting Ocular Cell Survival, Patent pending, 2004.

Ma P, Wang N, McKown RL, Raab, RW, Laurie GW (2007) Focus on Molecules: Lacritin., Exp Eye Res., In Press.

Wang, J., Wang, N., Xie, J., Walton, S.C., McKown, R.L., Raab, R.W., Ma, P., Beck, S.L., Coffman, G., Hussaini, I., and Laurie, G.W. (2006) Restricted epithelial proliferation by lacritin via PKCa-dependent NFAT and mTOR pathways., J. Cell Biol., 174 (5), 689-700.

Ma, P., Beck, S.L., Raab, R., McKown, R., Coffman, G., Utani, A., Chirico, W.J., Rapraeger, A., and Laurie, G.W. (2006) Heparanase deglycanation of syndecan-1 is required for binding of epithelial-restricted mitogen lacritin, J. Cell Biol., 174 (7), 1097-1106.

[Hangus]

Could this be the magic bullet? Are there any dry eye medicines available now which uses lacritin? If not when do you think the first commercial applications would be available for use if it is found to be a help with dry eyes?

[GordonLaurie]

lacritin application

We are optimistic that lacritin will be helpful. Unfortunately, clinical use could be years ahead.

[Rebecca Petris]

Thank you so much for the update.

[sazy123]

lacritin and my interesting situation with re signal receptors

Hi Gordonlaurie

I have sent you a private message. I think you will find it interesting..Its regarding my own situation, face pain and the link with singal receptors. I would be very grateful for 2 seconds of your time as i know you are very busy..

Many thanks Sazy123

[GordonLaurie]

Much progress has been made with lacritin and LacripepTM, including a Phase 2 trial now underway. See info and links below.

Primary Sjogren's Syndrome dry eye sufferers are needed for a 27 site clinical trial of 'LacripepTM'. LacripepTM is the natural tear- and ocular health-promoting portion of the tear protein 'lacritin' discovered in my University of Virginia lab with support from the National Eye Institute (https://www.ncbi.nlm.nih.gov/pubmed/11419941). Since lacritin is deficient in Sjogren's Syndrome dry eye (https://www.ncbi.nlm.nih.gov/pubmed/27711909), topical LacripepTM is a natural replacement therapy, much like insulin and type 1 diabetes. Trial sites with contact information are listed at http://www.tearsolutions.com/Clinical_Trial_Sites.html. Several additional sites will soon be added. Posted updates on LacripepTM and the trial are at https://www.facebook.com/LacritinAndDryEye/. Also check out the Lacritin Wikipedia page (https://en.wikipedia.org/wiki/Lacritin). [Commercial disclosure: I cofounded 'TearSolutions, Inc.' to move this discovery into the clinic].

[drytc1]

Will this medicine be used for sufferers due to MGD or just people with SS?

[bobXfr]

did lacripepTm help meibomian glands? will you do meibography at least for some patients in the trial?

The biology suggests that it may help meibomian glands, but there is no evidence to date. Meibography is not being performed, however attention is being paid to those with Meibomian Gland Disease with assessment of inflammation of the lid margin, number of orifices plugged, character of secretion and expressibility. Gordon.

That's what the Professor said when i asked him about MGD