Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease

Abstract

Purpose

To evaluate the safety and feasibility of injecting allogeneic adipose-derived mesenchymal stem cells (ASCs) into the lacrimal gland (LG) as a treatment of aqueous deficient dry eye disease (ADDE).

Methods

In this open-label, 5-visit clinical trial (baseline, treatment and weeks 1, 4 and 16) seven subjects with ADDE received one transconjunctival injection of allogeneic ASCs into the LG in one eye. The ASC product contained 22 million ASCs/ml and the injected volume was maximally 50% of the LG volume as determined on magnetic resonance imaging (MRI). Treatment related adverse events (AEs) were assessed at each visit (primary endpoint). Ocular Surface Disease Index (OSDI), tear osmolarity, tear film breakup time (TBUT), corneal staining (Oxford grade) and Schirmer's I test were assessed at each timepoint.

Results

No AEs related to the study treatment were observed. Mean follow-up time was 126 days after treatment. The mean OSDI score decreased from 58.9 ± 20.6 at baseline to 34.1 ± 21.6 (p < 0.002). In the study eye mean tear osmolarity decreased from 312.9 ± 10.4 to 291.6 ± 10.9 mosm/l (p < 0.002), mean TBUT increased from 3.7 ± 1.5 to 7.1 ± 1.9 s (p < 0.002), mean Schirmer's I test increased from 4.6 ± 0.7 to 8.1 ± 3.1 mm/5 min (p < 0.03), while mean Oxford grade showed a trend towards a decrease from 2.4 ± 0.7 to 1.3 ± 1 (p < 0.10).

Conclusion

Our trial suggests that injection of allogeneic ASCs into the LG is a safe and feasible treatment of severe ADDE. A randomized placebo-controlled trial aimed at elucidating the therapeutic effect of allogeneic ASCs in a larger patient cohort from our research group is currently underway.

Introduction

Dry eye disease (DED) is a common problem seen in patients all over the world with a reported prevalence of 5–50% [1]. The prevalence of DED in a Danish population has been reported to be 11% and increasing with age [2]. Symptoms of DED include ocular discomfort and blurred vision, which negatively impact visual function and quality of life. DED is subdivided into evaporative dry eye (EDE) with excessive evaporation from the tear film and aqueous-deficient dry eye (ADDE) with reduced lacrimal secretion from the lacrimal gland (LG), though often patients have a combination of both [3]. In the western world the most common cause of ADDE is Sjögren's syndrome (SS) which is a chronic autoimmune disorder characterized by inflammation and lymphocytic infiltration in the affected exocrine glands [4]. This exocrinopathy can be encountered alone in primary SS (pSS) or in the presence of another autoimmune disorder such as rheumatoid arthritis (secondary SS). Presently, a diagnosis of SS relies on a combination of clinical, histological, and immunological findings, in combination with relevant subjective symptoms (dry eyes and/or mouth) as stated in the “2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome” [5]. Current treatment options for ADDE are symptomatic as a curative treatment does not exist [6].

Mesenchymal stromal - or stem cells (MSCs) are multipotent stem cells with the capacity to differentiate into various cell types and have been shown to reduce inflammation and enhance tissue repair after transplantation in vivo [7,8]. The immunomodulatory effect of MSCs on the immune system can be mediated both through soluble factors and cell to cell interactions, however, the paracrine signaling pathways are considered the key mechanisms by which MSCs influence other cells. Several studies have reported therapeutic benefits of MSCs transplantation even though long-term engraftment of these cells could not be detected [9]. Allogeneic MSCs has the potential advantage as an “off-the-shelf” therapeutic agent, avoiding the cost of individual tissue collection and cell culture associated with autologous MSCs. Also the function of autologous MSCs has been proposed to be impaired in patients with comorbidities or advanced age [10]. An extensive number of clinical trials with allogeneic MSCs from various sources and targeting different diseases have been conducted and no adverse events related to an anti-donor immune response have been reported [11]. Adipose tissue-derived MSCs (ASCs) have gained considerable attention, as ASCs are readily available from the abdominal fat where it is easily collected and expanded ex vivo [12].

The substantial immunoregulatory and tissue reparative functions of MSCs in the setting of ocular surface disease have been clearly demonstrated [13]. Although the immunoregulatory mechanisms of MSCs in DED have not been clearly delineated, preliminary reports suggest that MSCs may protect the ocular surface against autoimmune mediated inflammation [14,15]. As in humans, canines are at risk of developing an immune-mediated inflammatory disease targeting the LGs which make canines a superior animal model of ADDE [16]. Two trials evaluating injection of allogeneic ASCs around the canine LG have been published and both found that this treatment was safe, increased tear production, and improved ocular surface signs up to 12 months after a single treatment [17,18].