A Highly Soluble Matrix Metalloproteinase‐9 Inhibitor for Potential Treatment of Dry Eye Syndrome

Abstract

Dry eye syndrome (DES) or keratoconjunctivitis sicca is an eye disease caused by the chronic lack of lubrication and moisture of the eye. The pathogenesis of DES involves the over-expression and over-activity of corneal Matrix Metalloproteinase 9 (MMP-9). We propose herein a new, non-symptomatic approach for the treatment of DES based on the inhibition of MMP-9 by a new highly soluble molecule, designed as PES_103 that has been shown to inhibit MMP-9 both in vitro and in vivo. The efficacy of PES_103 in vivo and the potential benefits of this treatment in restoring tear production were studied in this work using an animal model of reduced lacrimation. PES_103 did not show any significant corneal toxicity.Matrix metalloproteinases (MMPs) are a family of zinc containing hydrolases with a broad proteolytic specificity and large structural similarity [1]. These enzymes are involved in the degradation of several extracellular proteins including extracellular matrix components (ECM) and play a crucial role in tissue remodelling and in the regulation of different cellular activities [2]. An aberrant MMPs activity often promotes an excessive degradation of the ECM and could be responsible for the genesis of diseases such as inflammation, angiogenesis and cancer [3]. Recently, relevant ocular disorders such as proliferative diabetic retinopathy and dry eye syndrome (DES), or keratoconjunctivis sicca, have been associated with a significant increase in the concentration and activity of MMPs in the tear fluid [4-6]. In particular, DES has been associated with the over-expression and increased activity of corneal Matrix Metalloproteinase-9 (MMP-9 or Gelatinase B) [7], which has been shown to be both a marker and a promoter of eye dryness [8]. According to the work of Pflugfelder et al. [9], MMP-9 knockout mice do not develop DES, whereas the topical administration of active MMP-9 to such mice significantly increased corneal epithelial permeability.The 2007 Report of the Dry Eye WorkShop (DEWS) defined dry eye as an eye disease that results mostly in symptoms of discomfort, visual disturbance and tear film instability, with potential damage to the ocular surface that affects about 20% of the American population and 75% of the over-65-year population [10,11]. DES can be caused by a decrease in tear production or an increase in tear film evaporation, hence being represented by reduced lacrimation models. Persistent dryness, burning and a sandy-gritty eye irritation are the most common symptoms associated with DES and, in general, get worse as the day goes on [12]. Generally, both eyes are affected by DES and the physical damage occurs mainly at the corneal level. The aetiology of this syndrome is manifold, from the normal ageing process, to the effects of different drugs [13], to climatic factors together with daily routines and working-related features, such as standing in front of a computer screen, the use of air conditioning or of contact lenses [14,15]. DES is even a symptom of many systemic diseases. In particu...

Clinical and Molecular Inflammatory Response in Sjögren Syndrome–Associated Dry Eye Patients Under Desiccating Stress

“…46 Additionally, other authors have shown in-vivo benefits of using MMP-9 inhibitors for restoring tear production. 47 In the present study we also found consistent associations between the increase in IL-1RA tear levels and the worsening of the corneal staining, in addition to the relationship between the decrease in Schirmer test and the increase of IL-6, IL-8 and MMP-9 tear levels. These findings provide more evidence (at least in SS patients) to support the relationship existing between the response of the lacrimal functional unit in terms of tear molecule secretion and the clinical signs commonly observed in the slit lamp examination.…”

The Matrix Metalloproteinase 9 Point-of-Care Test in Dry Eye

“…With administration of PES_103, both tear volume and MMP-9 activity were restored to physiological levels. 32 …”

The Key Role of VEGF in the Cross Talk between Pterygium and Dry Eye and Its Clinical Significance

“…The function of MMP-9 in the onset of dry eye has received a great deal of attention [43], and researchers have proposed that MMP-9 might become a diagnostic marker of dry eye at the molecular level [44]. Recently, a study inhibited MMP-9 as a new target for dry eye treatment [45]. In addition, MMP-9 plays important roles in the onset of pterygium, it not only disrupts the epithelial barrier to facilitate the invasion of pterygium into a transparent cornea, but also promotes the development and postoperative recurrence of pterygium [7,21].…”