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Trehalose: A novel treatment for dry eye
This new approach is both a bioprotectant and an osmoprotectant.
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As ophthalmologists and clinical scientists, we continually search for new approaches to the treatment of dry eye; we have learned that prescription therapeutics such as cyclosporine and lifitegrast, palliative measures such as artificial tears, and in-office treatments such as microblepharoexfoliation and thermal pulsation therapy can all work together to enhance the clinical effect. In other words, 1 + 1 often equals 3. I recently discovered that there is a new entrant into the field of dry eye treatment, a powerful excipient in artificial tears with a long track record as a powerful anti-desiccant.
Trehalose
Trehalose is a novel treatment that has been used internationally to treat dry eye; it is now being introduced to the U.S. It is a natural alpha-linked disaccharide formed by an alpha, alpha-1, 1-glucoside bond between two alpha-glucose units. Trehalose is found abundantly in nature; it is both a bioprotectant and an osmoprotectant. It protects corneal cells from desiccation and high osmolarity by fortifying cell membranes and preventing the denaturation of proteins in the absence of water.
In 1702, Antonie van Leeuwenhoek discovered that he could revive a completely dried insect with a small amount of water; this insect was thought to contain trehalose. Brine shrimp (aka, sea monkeys) are also able to survive desiccation because of the presence of trehalose. Similarly, the Rose of Jericho can survive for years without water, in a dormant state, and come back to life within hours when re-exposed to water; this is due to the presence of trehalose.
Trehalose has already been used extensively in major industries such as food, cosmetics and medicine. It is currently used as an excipient in the formulations of Herceptin (trastuzumab, Genentech), Avastin (bevacizumab, Genentech), Lucentis (ranibizumab, Genentech) and Advate (antihemophilic factor (recombinant), Shire).
In Matsuo’s 2001 lab study published in British Journal of Ophthalmology, trehalose reduced the number of dead human corneal epithelial cells after 30 minutes of desiccation. In Matsuo’s 2002 clinical study published in Ophthalmology, trehalose significantly decreased rose bengal staining and improved tear film stability after both 2 and 4 weeks of treatment.
In a dry eye mouse model, in Chen’s 2009 paper in Experimental Eye Research, trehalose significantly increased tear production, decreased corneal staining and decreased epithelial cell apoptosis at day 14 of treatment vs. control.
How it works
So how does trehalose work? In Jain and Roy’s 2009 review paper in Protein Science, they proposed three theories:
1. The immobilization theory: Trehalose forms a cocoon-like structure around the protein, much like when amber encases an insect.
2. The preferential exclusion theory: Trehalose keeps water out of the protein, which increases its compactness and consequently its stability.
3. The water replacement theory: Trehalose substitutes for water, stabilizing its 3-D structure.
And there may be even more pathways by which trehalose prevents desiccation. In Li’s 2012 mouse study in Molecular Vision, he demonstrated that trehalose restored ocular surface integrity, suppressed inflammatory markers and suppressed keratinization of the corneal epithelium.
In Baudouin’s 2013 review article in Ocular Surface, he stated that osmoprotectants in dry eye disease (DED) may directly protect cells against hyperosmolarity and thereby promote the exit from the vicious circle of DED physiopathology.
In Hill-Bator’s 2014 laboratory study in BioMed Research International, commercially available lubricating drops in the European Union were compared in cultured human corneal epithelial cells. Assays of living and dead cells demonstrated that trehalose-containing eye drops showed the highest efficiency in prevention of cell death from desiccation.
In Aragona’s 2014 study in Scientific World Journal of corneas treated with alcohol for LASEK, trehalose administration better preserved corneal morphological and morphometric features compared with controls.
In Schmidl’s 2015 publication in Cornea, trehalose-containing drops increased patients’ tear film thickness as measured by OCT, after instillation of only one drop, up to 240 minutes compared with drops without trehalose.
In Chiambaretta’s 2017 study in European Journal of Ophthalmology, 105 patients were treated three to six times a day for 84 days with either hyaluronic acid (HA) with trehalose vs. HA only. The Oxford grading scale was used at day 35. Questionnaires, Schirmer testing, tear film breakup time and conjunctival hyperemia scores were compared. The authors concluded that HA with trehalose was safe and effective, and gave better patient satisfaction. They felt that it was a therapeutic advancement in the treatment of moderate to severe DED.
In Mateo Orobia’s 2017 study in Clinical Ophthalmology, he found an improvement in LASIK results with 3% trehalose drops vs. control. The most relevant results of this study are those concerning the vital stains: The authors found larger differences in the variables that evaluate cell vitality between the two groups, in favor of the trehalose-containing drops.
In conclusion, numerous publications and clinical reports support the clinical utility of including the powerful anti-desiccant trehalose in dry eye treatments, particularly artificial tears. The U.S. is just beginning to enjoy the benefits of this breakthrough, with trehalose-containing over-the-counter lubricants appearing on the market.
- References:
- Aragona P, et al. Scientific World Journal. 2014;doi:10.1155/2014/717835.
- Baudouin C, et al. Ocul Surf. 2013;doi:10.1016/j.jtos.2013.07.003.
- Chen W, et al. Exp Eye Res. 2009;doi:10.1016/j.exer.2009.03.015.
- Chiambaretta F, et al. Eur J Ophthalmol. 2017;doi:10.5301/ejo.5000836.
- Hill-Bator A, et al. Biomed Res Int. 2014;doi:10.1155/2014/292139.
- Jain NK, et al. Protein Sci. 2009;doi:10.1002/pro.3.
- Li J, et al. Mol Vis. 2012;18:317-329.
- Matsuo T. Br J Ophthalmol. 2001;doi:10.1136/bjo.85.5.610.
- Matsuo T, et al. Ophthalmology. 2002;doi:10.1016/S0161-6420(02)01219-8.
- Orobia M, et al. Clin Ophthalmol. 2017;doi:10.2147/OPTH.S125203.
- Schmidl D, et al. Cornea. 2015;doi:10.1097/ICO.0000000000000358.
- For more information:
- Marguerite B. McDonald, MD, FACS, can be reached at Ophthalmic Consultants of Long Island, 360 Merrick Road, Lynbrook, NY 11563; email: margueritemcdmd@aol.com.
Disclosures: McDonald reports she is a consultant for Akorn. Fumuso reports no relevant financial disclosures.