Shimmura Shigeto

A first-in-human investigator-initiated clinical study of a corneal endothelial cell substitute (CLS001) derived from a clinical-grade induced pluripotent stem cell (iPSC) line shows improvement of visual acuity and corneal stromal edema, with no adverse events for up to 1 year after surgery for the treatment of bullous keratopathy. While preclinical tests, including multiple whole-genome analysis and tumorigenicity tests adhering to the Food and Drug Administration (FDA) draft guidelines, are negative, an additional whole-genome analysis conducted on transplanted CLS001 cells reveals a de novo in-frame deletion of exon22 in the EP300 gene. No adverse events related to the mutation are observed. Our study demonstrates the feasibility of using iPSC-derived cells to replace donor transplant for bullous keratopathy, while shedding light on risk management of gene mutation in cell products. Further follow-up is required for long-term analysis of clinical safety and efficacy.

PURPOSE: This study explores the application of adipose-derived mesenchymal stromal cells (adMSCs) as a therapy for ocular inflammatory diseases utilizing a chronic GVHD model. METHODS: Human adMSCs were administered via subconjunctival injection into mice with chronic ocular GVHD. Clinical scores and changes in T cell populations were analyzed. RESULTS: The study showed significant improvement in corneal integrity, including epithelial damage, opacity, thickness, and structure, after subconjunctival adMSC transplantation. Additionally, adMSC transplantation increased CD45+ and Foxp3+ Tregs while decreasing CD4+ T cells, 1IL17A+ Th17 cells, and IFNγ+ Th1 cells in local cervical lymph nodes. Moreover, adMSC-conditioned media enhanced wound closure and cell migration toward the wound bed in vitro. The cells disappeared within a week suggesting that trophic factors were involved. CONCLUSION: The dual benefit of adMSCs in immune-related ocular disorders underscores their potential for clinical application. This study focuses on subconjunctival delivery, effects of adMSCs and migration post-injection, with implications for optimizing cellular therapy application. The observed dual action, combining immunomodulation and tissue repair enhancement, underscores holistic approach of adMSC therapy in regenerative medicine, making it a potent treatment for diseases involving inflammation and tissue damage in the ocular surface.

Rationale: Patients with atopic dermatitis undergoing penetrating keratoplasty (PKP) face a high risk of postoperative complications. Endothelial keratoplasty may be a safer alternative for such patients, including those with abnormal anterior chamber anatomy. Patient concerns: 3 male patients, aged 33 to 44, presented with blurred vision at Keio University Hospital. Diagnosis: Bullous keratopathy was diagnosed through slit-lamp examination and specular microscopy. Two patients had well-controlled systemic atopic dermatitis, while 1 had blepharitis associated with atopic dermatitis. Two patients had peripheral anterior synechia, and 2 had undergone glaucoma surgery before keratoplasty. Interventions: Non-Descemet stripping endothelial keratoplasty (nDSAEK) was performed by a single surgeon. Outcomes: The best-corrected visual acuity ranged from 0.7 to 1.5 logMAR before surgery and from 0.2 to 2.3 logMAR after surgery. One year post-surgery, the graft remained clear in 2 cases; however, in the case of repeated glaucoma surgeries after nDSAEK, the graft became edematous. Corneal endothelial cell density was 1586 and 1988 cells/mm² in 2 cases and undetectable in the failed case. The follow-up period ranged from 2.5 to 9 years. Lessons: Despite the presence of peripheral anterior synechia or prior glaucoma surgery, some patients experienced a favorable long-term postoperative course following nDSAEK. This procedure may offer a safer alternative for treating patients with atopic dermatitis who have ocular complications that present a high risk for PKP.

PURPOSE: Aging is a well-established risk factor for meibomian gland dysfunction (MGD). We previously reported an accelerated cellular senescence phenomenon in the lacrimal glands of a murine model of chronic graft-versus-host disease (cGVHD). Herein, we aimed to elucidate the relationship between cellular senescence and MGD in cGVHD mice, utilizing the senolytic agent ABT-263. METHODS: A cGVHD mouse model was established through allogeneic bone marrow transplantation (BMT) from B10.D2 to BALB/c mice. Subsequently, cGVHD mice were treated with either ABT-263 or vehicle. The eyelids of recipients were analyzed at 4-week intervals post-BMT in both groups. RESULTS: Meibomian gland (MG) area was significantly smaller in cGVHD mice than in syngeneic control mice. ABT-263-treated mice retained a significantly larger MG area than their vehicle-treated counterparts. Pathological and immunohistochemical examinations revealed significant reductions in eyelid tissue inflammation and pathological fibrosis in the ABT-263 group compared to that in the vehicle-treated group. Additionally, expression of DNA damage markers, senescent cell markers, and senescence-associated secretory phenotype (SASP) factors was elevated in the eyelids of cGVHD mice compared with that in syngeneic mice. The expression of these cellular senescence-associated molecules was considerably suppressed in ABT-263-treated eyelids compared to that in vehicle-treated ones. CONCLUSIONS: Cellular senescence, along with expression of SASP factors, exhibited increased activity in the eyelids, particularly in the MGs of cGVHD mice. ABT-263 mitigated the severity of MGD. These findings highlight the potential of targeting cellular senescence as an effective approach for MGD treatment in cGVHD.

Regenerative medicine is a highly anticipated field with hopes to provide cures for previously uncurable diseases such as spinal cord injuries and retinal blindness. Most regenerative medical products use either autologous or allogeneic stem cells, which may or may not be genetically modified. The introduction of induced-pluripotent stem cells (iPSCs) has fueled research in the field, and several iPSC-derived cells/tissues are currently undergoing clinical trials. The cornea is one of the pioneering areas of regenerative medicine, and already four cell therapy products are approved for clinical use in Japan. There is one other government-approved cell therapy product approved in Europe, but none are approved in the USA at present. The cornea is transparent and avascular, making it unique as a target for stem cell therapy. This review discusses the unique properties of the cornea and ongoing research in the field.