Mesenchymal stem cell therapy in aqueous deficient dry eye disease

Michael Møller-Hansen*

*Corresponding author for this work

Abstract

Dry eye disease (DED) is characterized by ocular dryness, irritation and blurred vision and has a significant impact on the patient's quality of life. This condition can be particularly severe in patients with aqueous deficient dry eye disease (ADDE) due to Sjögren's syndrome (SS), an autoimmune disease that affects the lacrimal and salivary glands. Current treatments for ADDE are often limited to symptomatic relief. A literature review was conducted to explore the current surgical interventions used or tested in humans with ADDE (I). These interventions include procedures involving the eyelids and tear ducts, transplantation of amniotic membrane or salivary glands, injections around the tear ducts and cell-based injections into the lacrimal gland (LG). Each treatment has its advantages and disadvantages; however, treating dry eyes in patients with SS presents a particular challenge due to the systemic nature of the disease. Moreover, there is a need for new therapeutic options. Mesenchymal stem cells (MSCs) are a type of stem cell that have shown promise in regenerating damaged tissue and reducing inflammation in various diseases. Previous studies in animal models have suggested that MSCs could be effective in treating ADDE. Thus, this thesis aims to investigate the safety and efficacy of injecting MSCs into the LG as a treatment option for patients with ADDE secondary to SS. The study also aims to see this treatment in light of existing and novel investigational treatment options. The clinical studies conducted for this thesis are the first of their kind in humans. MSCs derived from healthy donors' adipose tissue (ASCs) were cultured in a laboratory, frozen and thawed ready for use. In the safety study, we performed the first human trial involving the administration of a single injection of ASCs into the LG of one eye in seven patients suffering from severe ADDE (II). The primary objective was to test the safety of this treatment, while the secondary objective was to assess improvements in subjective and objective signs of dry eye. The results of the trial showed no serious side effects within 4 months of follow-up after treatment. On average, there was a 40% reduction in dry eye symptoms assessed with the Ocular Surface Disease Index (OSDI) questionnaire. Additionally, in the treated eye, there was a significant decrease in tear osmolarity, an increase in tear film stability and an increase in tear production. To further investigate the efficacy of this treatment, our research group performed a clinical, randomized study aiming to compare the ASC injection into the LG with the injection of a vehicle (the excipient in which the ASCs are dissolved) and observation (no intervention) (III). The study involved 20 subjects receiving ASC injection, 20 subjects receiving vehicle injection and 14 patients being observed without intervention. The subjects were examined to assess the outcomes with a 12-month follow-up after treatment. Both intervention groups showed a significant reduction in subjective dry eye symptoms of approximately 40%. This improvement was evident at the 1-week follow-up and persisted until the 12-month follow-up. The observation group did not experience any change in OSDI score. The ASCs group exhibited a significant mean increase in non-invasive tear break-up time (NIKBUT) of 6.48 s (149%) at the four-week follow-up, which was significantly higher than that in the vehicle group (p = 0.04). Moreover, the ASCs group showed a significant increase in NIKBUT compared to that in the observation group at the 12-month follow-up (p = 0.004). In both the ASCs and vehicle group, a significant increase in Schirmer test scores at the 4-month follow-up and the 12-month follow-up was observed. In conclusion, this thesis contributes valuable findings with a new treatment option for patients with dry eye disease. Injection of ASCs into the LG was shown to be safe and to improve subjective dry eye symptoms and specifically the tear film stability in patients with ADDE due to SS. Compared to other treatment modalities of ADDE, this treatment has greater potential, as ASCs could potentially be used as an anti-inflammatory therapeutic option for managing DED of other causes as well. RESUMÉ (DANISH SUMMARY): Tørre øjne, karakteriseret ved tørhedsfornemmelse og irritation af øjnene samt sløret syn, har en betydelig indvirkning på patientens livskvalitet. Denne tilstand kan vaere saerligt alvorlig hos patienter med nedsat tåreproduktion (ADDE) som følge af Sjögrens syndrom (SS), en autoimmun sygdom, der påvirker tårekirtlerne og spytkirtlerne. Nuvaerende behandlinger for ADDE er ofte begraenset til symptomlindring. Vi gennemførte en litteraturgennemgang for at undersøge, hvilke nuvaerende kirurgiske behandlingsmetoder, der anvendes eller testes hos patienter med ADDE (I). Disse interventioner inkluderer procedurer, der involverer øjenlåg og tårekanaler, transplantation af amnionhinde eller spytkirtler, injektioner omkring tårekanalerne samt cellebaserede injektioner i tårekirtlen. Hver behandling har sine fordele og ulemper, men behandling af tørre øjne hos patienter med SS udgør en saerlig udfordring på grund af sygdommens systemiske udbredning, og der er behov for nye behandlingsmuligheder. Mesenkymale stamceller (MSCs) er en type stamcelle, der har vist lovende resultater med hensyn til at regenerere beskadiget vaev og reducere inflammation i forskellige sygdomme. Tidligere undersøgelser i dyremodeller har indikeret, at MSCs kan vaere en effektiv behandling af ADDE. Denne afhandling har til formål at undersøge sikkerheden og effekten af injektion af MSCs i tårekirtlen som en mulig behandling til patienter med ADDE som følge af SS. Afhandlingen sigter også mod at sammenligne denne behandling med andre eksisterende, kirurgiske behandlingsmuligheder af ADDE. Som led i dette projekt udførte vi de første kliniske forsøg af sin art i mennesker. MSCs fra raske donorers fedtvaev (ASCs) blev dyrket i et laboratorium, frosset ned og er optøet klar til brug. Det første mål var at teste sikkerheden ved denne behandling og sekundaert at undersøge behandlingens effekt. For at undersøge dette modtog syv forsøgspersoner med svaer ADDE én injektion med ASCs i tårekirtlen på det ene øje (II). Resultaterne af forsøget viste ingen alvorlige bivirkninger inden for fire måneders opfølgning efter behandlingen. I gennemsnit fandt vi yderligere en 40% reduktion i symptomer på tørre øjne vurderet med et spørgeskema, og en markant stigning i tåreproduktionen og af tårefilmens stabilitet i det behandlede øje. For yderligere at undersøge effekten af denne behandling udførte vi et klinisk, randomiseret forsøg med det formål at sammenligne injektion af ASCs i tårekirtlen med injektion af en kontrolopløsning (vaesken, hvor stamcellerne var opløst) og observation (ingen intervention) (III). Studiet omfattede 20 forsøgspersoner, der modtog ASC-injektion, 20 forsøgspersoner, der modtog injektion af kontrolopløsningen, og 14 forsøgspersoner i observationsgruppen. Forsøgspersonerne blev undersøgt med en opfølgningstid på 12 måneder efter behandling. Begge interventionsgrupper viste en betydelig reduktion på ca. 40% i subjektive symptomer på tørre øjne. Denne forbedring var betydelig allerede ved opfølgning efter en uge og varede ved 12 måneder efter behandling. Observationsgruppen oplevede ingen betydelig aendring i symptomer. ASCs gruppen viste desuden en signifikant stigning i tårefilmsstabiliteten (NIKBUT) på 6,48 sekunder (149%) ved opfølgning efter fire uger, hvilket var markant højere end efter injektion af kontrolopløsning (p = 0,04). Desuden viste ASCs gruppen en betydelig stigning i NIKBUT sammenlignet med observationsgruppen ved opfølgning efter 12 måneder (p = 0,004). Både injektion af ASCs og kontrolopløsning medførte en betydelig stigning i tåreproduktionen ved opfølgning fire måneder og 12 måneder efter behandling. Denne afhandling bidrager med vigtige resultater inden for en ny behandlingsmulighed af tørre øjne. Injektion af ASCs i tårekirtlen viste sig at vaere sikker, forbedrede subjektive symptomer på tørre øjne og øgede saerligt tårfilmens stabilitet hos patienter med ADDE på grund af SS. Sammenlignet med andre behandlingsmuligheder for ADDE har denne behandling vist et stort potentiale. ASCs kan muligvis også bruges som en anti-inflammatorisk behandling af tørre øjne af andre årsager i fremtiden.

Original languageEnglish
JournalActa Ophthalmologica
Volume101 Suppl 277
Pages (from-to)3-27
Number of pages25
ISSN1755-375X
DOIs
Publication statusPublished - Oct 2023

Keywords

  • Dry Eye Syndromes/therapy
  • Humans
  • Inflammation
  • Male
  • Mesenchymal Stem Cell Transplantation
  • Mesenchymal Stem Cells
  • Quality of Life
  • Randomized Controlled Trials as Topic

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