First-in-human autologous implantation of genetically modified adipocytes expressing LCAT for the treatment of familial LCAT deficiency.

Background: Familial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a severe inherited disease without effective treatment. Patients with FLD develop severe low HDL, corneal opacity, hemolytic anemia, and renal injury. Objective: We developed genetically modified adipocytes (GMAC) secreting LCAT (LCAT-GMAC) for ex vivo gene therapy. GMACs were prepared from the patient's adipocytes to express LCAT by retroviral gene transduction to secrete functional enzymes. This study aimed to evaluate the safety and efficacy of LCAT-GMAC implantation in an FLD patient. Methods: Proliferative preadipocytes were obtained from a patient using a ceiling culture and retrovirally transduced with LCAT. After obtaining enough cells by expansion culture of the transduced cells, the resulting LCAT-GMACs were implanted into a patient with FLD. To evaluate the safety and efficacy, we analyzed the outcome of the autologous implantation for 24 weeks of observation and subsequent 240 weeks of the follow-up periods. Results: This first-in-human autologous implantation of LCAT-GMACs was shown to be safe by evaluating adverse events. The LCAT-GMAC implantation increased serum LCAT activity by approximately 50% of the baseline and sustained over three years. Consistent with increased LCAT activity, intermediate-density lipoprotein (IDL) and free cholesterol levels of the small and very small HDL fractions decreased. We found the hemoglobin/haptoglobin complex in the hemolyzed pre-implantation sera of the patient. After one week of the implantation, the hemoglobin/haptoglobin complex almost disappeared. Immediately after the implantation, the patient's proteinuria decreased temporarily to mild levels and gradually increased to the baseline. At 48 weeks after implantation, the patient's proteinuria deteriorated with the development of mild hypertension. By the treatment with antihypertensives, the patient's blood pressure normalized. With the normalization of blood pressure, the proteinuria rapidly decreased to mild proteinuria levels. Conclusions: LCAT-GMAC implantation in a patient with FLD is shown to be safe and appears to be effective, in part, for treating anemia and proteinuria in FLD.

The Case of IgG4-Related Ophthalmic Disease with Perivascular Lesions of Superior Ophthalmic Vein Associated with Optic Nerve Disturbance.

A 61-year-old man with hyperthyroidism had exophthalmos with dilated conjunctival vessels in both eyes. Magnetic resonance imaging showed that the superior ophthalmic veins had a funicular-like appearance. Cerebral angiography showed no blood flow from both internal carotid arteries to the cavernous sinus, thus excluding a carotid-cavernous fistula. Blood tests showed an elevation of IgG4 (281 mg/dl), and a IgG4-related ophthalmic disease was considered. Steroid pulse therapy was performed, and all of the abnormal findings were improved. We concluded that this was a rare case of IgG4-related ophthalmic disease with perivascular lesions of the superior ophthalmic vein associated with optic nerve disturbance.

A Case of Conjunctival Amyloidosis with Repeated Subconjunctival Hemorrhage.

Conjunctival amyloidosis is a very rare disease, and its presence may be a sign of systemic amyloidosis. We present our ocular and systemic findings in a patient with conjunctival amyloidosis. A 43-year-old man had repeated subconjunctival hemorrhages (SCHs) for two years and was referred to the Chiba University Hospital. He had comprehensive ophthalmological and systemic examinations to determine the cause of the SCHs. His visual acuities were 1.2 OU, and the intraocular pressures were 13-14 mmHg OU. Magnetic resonance imaging was normal. Initially, the SCH was the only abnormality. After 3 months, the SCH had partially cleared, and a pink mass was detected in the superior area of the subconjunctiva. Partial biopsy and histopathological examinations showed a greenish birefringence and dichroism under polarized light illumination. The birefringence was located in amyloid fibers. Immunofixation electrophoresis detected λ-light chain abnormality in the ocular biopsy specimen but systemic examinations did not find any lesions. Multiple myeloma was ruled out, and the patient is being followed closely to detect any early signs of systemic amyloidosis. Because repeated SCHs might be initial signs of systemic amyloidosis, patients with conjunctival amyloidosis should be comprehensively examined for systemic amyloidosis because of its poor life prognosis.

Improvement of central retinal sensitivity six months after topical isopropyl unoprostone in patients with retinitis pigmentosa.

AIMS: Isopropyl unoprostone (IU), a maxi-K channel activator, is used topically to treat glaucoma, and has been reported to have neuroprotective effects on retinal neurons in vitro and in vivo. The purpose of this non-comparative pilot study was to determine whether topical IU will alter the sensitivity of the central retina in patients with retinitis pigmentosa (RP). SETTINGS AND DESIGN: Non-comparative pilot study. MATERIALS AND METHODS: IU was given topically twice a day for 6 months to both eyes of 30 patients with typical RP. The visual acuity was measured with a Japanese Snellen chart, and the mean retinal sensitivities were obtained by fundus-related microperimetry (MP-1). The mean deviation (MD) of the visual field was determined with a Humphrey field analyzer (HFA). All measurements were made before and 6 months after the treatment. STATISTICAL ANALYSIS USED: Wilcoxon and the Mann-Whitney U tests (SPSS, SPSS Inc., Chicago, IL). RESULTS: After the treatment, the mean retinal sensitivity within the central 2° and 10° improved significantly from 12.3 ± 4.8 dB to 14.7 ± 5.5 dB (P = 0.001) and from 9.1 ± 5.4 dB to 11.0 ± 6.2 dB (P = 0.001), respectively. CONCLUSIONS: These short-term results suggest topical IU can improve the central retinal sensitivity in RP patients. It will be necessary to examine longer treatment periods in a controlled study to determine the effectiveness of topical IU in RP patients.

Corneal changes in diabetes mellitus.

Diabetes mellitus is a major disease worldwide, and the prevalence of diabetes has risen significantly in the past several decades. Although one of the major complications of diabetic eyes is diabetic retinopathy (DR), corneal diseases can not only develop in diabetic patients but are also difficult to manage. Diabetic neurotrophic keratopathy is a component of diabetic polyneuropathy and is recognized to be the cause of the morbidity of the cornea in diabetic patients. In addition, corneal endothelial cell damage can cause disturbances in the management of proliferative DR before and after surgeries because of endothelial decompensation with bullous keratopathy. However, there have been only a limited number of studies that have focused on the importance of corneal diseases in diabetic patients. This review describes the pathophysiological roles of different factors that have been found to be causative factors of diabetic corneal keratopathy and endothelial cell dysfunction in diabetic patients. In addition, the clinical features of the corneal changes in diabetic patients and recent studies related to the development of therapies for the management of corneal diseases are presented.

Relationship between vision-related quality of life and microperimetry-determined macular sensitivity in patients with retinitis pigmentosa.

PURPOSE: The aim of our study was to determine the relationship between vision-related quality of life (VRQOL) following the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) and the macular sensitivity determined by microperimetry in patients with retinitis pigmentosa (RP). METHODS: The Japanese version of the NEI VFQ-25 was used to assess the VRQOL of 30 patients with typical RP whose decimal visual acuity was ≥0.6. The mean retinal sensitivity within the central 10° was determined by fundus-related microperimetry (MP1). The correlation between the mean of the total composite NEI VFQ-25 score and MP1-determined macular sensitivity was determined. RESULTS: Mean NEI VFQ-25 score was 69.4 ± 14.5 (range 34.6-90.3) in RP patients. There was a significant positive correlation between mean NEI VFQ-25 score and mean retinal sensitivity within 10° (r = 0.673, P = 0.0003). CONCLUSION: The significant correlation between macular sensitivity and VRQOL measured with the NEI VFQ-25 indicates that sensitivity in the macular area is an important consideration in using VRQOL with RP patients.