Intraperitoneal chromophore injections delay early-onset and rapid retinal cone degeneration in a mouse model of Leber congenital amaurosis.

Highly expressed in the retinal pigment epithelium (RPE), the RPE-specific 65-kDa (RPE65) enzyme is indispensable to generate 11-cis-retinal (11cRAL), a chromophore for rhodopsin and cone photopigments. RPE65 deficiency can lead to Leber congenital amaurosis type 2 (LCA2), in which the isomerization of photobleached all-trans-retinal into photosensitive 11cRAL is blocked, ultimately causing severe retinal dysfunction and degeneration. The related mouse models, which are constructed through gene knockout or caused by spontaneous mutations, morphologically present with early-onset and rapid retinal cone cells degeneration, including loss of short-wavelength-sensitive cone opsins (S-opsins) and mislocalization of medium-wavelength-sensitive cone opsins (M-opsins). Studies have shown that routine Rpe65 gene replacement therapy, mediated by an adeno-associated virus (AAV) vector, can restore RPE65 protein. However, AAV transfection and Rpe65 transgene expression require at least one to two weeks, and the treatment cannot fully block the early-onset cone degeneration. To determine the feasibility of delaying cone degeneration before gene therapy, we investigated the impact of 11cRAL treatment in an early-age LCA2 retinal degeneration 12 (rd12) mouse model. Similar to human patients, the mouse model carries a spontaneous mutation in the Rpe65 gene, which results in disrupted endogenous 11cRAL regeneration. We found that RPE65 deficiency did not notably affect rodent retinal vessels. Under red light illumination, the rd12 mice were intraperitoneally injected with exogenous 11cRAL from postnatal day (P) 14 to P21. Three days after the last injection, a notable recovery of retinal function was observed using scotopic and photopic electroretinograms. Using optical coherence tomography and histological analyses of the deficient retinas, we found changes in the thickness of the photoreceptor outer segment (OS); this change could be rescued by early 11cRAL treatment. In addition, the treatment notably preserved M- and S-opsins, both of which maintained appropriate localization inside cone cells, as shown by the wild-type mice. In contrast, the age-matched untreated rd12 mice were characterized by retinal S-opsin loss and M-opsin mislocalization from the photoreceptor OS to the inner segment, outer nuclear layer, or outer plexiform layer. Notably, 11cRAL treatment could not maintain retinal function for a long time. Ten days after the last injection, the rod and M-cone electroretinograms significantly decreased, and S-cone responses almost extinguished. Our findings suggest that early 11cRAL treatment is useful for restoring retinal function and rescuing morphology in the rd12 mouse model, and the early-onset and rapid cone degeneration can be delayed before gene therapy.

Hyalurosome gene regulation and dose-dependent restoration of skin atrophy by retinaldehyde and defined-size hyaluronate fragments in dermatoporosis.

BACKGROUND: Dermatoporosis is an emerging clinical condition caused by chronological skin aging, long-term sun exposure and chronic use of corticosteroids; however, genomic expression in dermatoporosis and the efficacy of different therapeutic approaches to prevent and treat dermatoporosis have not been investigated so far. OBJECTIVE: We examined the possible effect of topical retinaldehyde (RAL) and defined-size hyaluronate fragments (HAFi) on the expression of hyalurosome genes potentially involved in the pathogenesis of dermatoporosis. We also explored the effect of different concentrations of HAFi on skin thickness. METHODS: 13 persons were separated into a young control group (n = 8) and a dermatoporosis group (n = 5). Topical treatment of both groups with a combination of 0.05% RAL and 1 or 0.2% HAFi was applied on the forearm twice daily for 30 days. Forearm skin biopsies of both groups were performed before and after application. Hyalurosome genes CD44, heparin-binding epidermal growth factor (HB-EGF), ErbB1, hyaluronate synthase 3 (HAS3) and Hyal2 were chosen as potential markers of dermatoporosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed for quantification of mRNA expression of the target hyalurosome genes. Measurement of forearm skin thickness before and after treatment was performed by ultrasonography. Analysis of the results was done by Student's t test. A p value <0.05 was considered statistically significant. RESULTS: In qRT-PCR analysis the relative expression of hyalurosome (CD44, HAS3, HB-EGF) genes was found to be reduced in patients prior to topical treatment and to be notably increased following treatment. The reduced expression of CD44 and HAS3 in patients was specifically restored in dermatoporotic patients after treatment. No difference in skin thickness was observed in controls after treatment. The treatment caused a significant increase in skin thickness in dermatoporotic patients. This increase was more significant with 1% HAFi when compared to 0.2% HAFi. RAL and HAFi also caused a significant reduction in purpuric lesions in patients with dermatoporosis. CONCLUSION: Our results indicate that topically applied RAL and HAFi regulate hyalurosome gene expression in dermatoporosis and that they show a dose-dependent effect on the correction of skin atrophy in dermatoporotic patients.

Improvement of visual performance with intravitreal administration of 9-cis-retinal in Rpe65-mutant dogs.

OBJECTIVE: To determine the efficacy of intravitreal administration of 9-cis-retinal in restoring visual function in Rpe65-mutant dogs. METHODS: Intravitreal injection of 9-cis-retinal was administered in 1 eye of 7 Rpe65-/- dogs at a range of ages. Electroretinogram analysis and testing of visual performance was used to evaluate outcomes after a single injection and in 2 dogs after a second injection in the same eye. RESULTS: In 5 of 7 injected dogs, 9-cis-retinal injection resulted in increased rod electroretinogram responses and improved functional vision. Three injected dogs exhibited increased 33-Hz flicker amplitudes characteristic of cone-mediated responses. Electroretinogram improvement was no longer evident by week 10 postinjection in 1 dog monitored over time. A second injection of 9-cis-retinal was performed in the same eye of 2 of the 7 dogs and also resulted in rescue of visual function. CONCLUSION: Our findings establish that 9-cis-retinoid therapy can restore visual function in a canine model of human disease resulting from RPE65 mutations. CLINICAL RELEVANCE: These positive proof-of-principle results provide support for the development of intravitreal devices for sustained delivery of 9-cis-retinal as a therapy for conditions resulting from failure of the visual cycle.

Ultrasound imaging demonstration of the improvement of non-ablative laser remodeling by concomitant daily topical application of 0.05% retinaldehyde.

BACKGROUND: Retinaldehyde has been proven to be effective in the reduction of facial wrinkles. It has also demonstrated its usefulness when used before and after laser skin resurfacing. OBJECTIVE: A monocentric, comparative, randomized, double-blind study was performed to evaluate the efficacy of retinaldehyde versus excipient in combination with non-ablative laser remodeling treatment. METHODS: A total of 16 female patients (mean age 45 years) were enrolled for neck line and forehead rhytid treatment. They were randomly assigned into two groups. The RAL group (eight patients) was treated with a non-ablative laser (1540 nm Er:glass, 10 J/cm2 per pulse, three pulses, 2 Hz repetition rate, 4 mm spot, +5 degrees C cooling) and daily topical application of 0.05% retinaldehyde immediately after the first laser treatment and up to 3 months after the fifth treatment. The CTRL group (eight patients) was treated under similar conditions, except with a daily application of excipient. The thickness of the skin (forehead and neck) was measured by ultrasound imaging before the first treatment, 1 month after the third treatment, 1 month after the fifth treatment and 3 months after the fifth treatment. RESULTS: An increase of dermal thickness was observed for all patients treated by laser (groups RAL and CTRL) on the forehead and neck. However, the increase was greater for the RAL group (retinaldehyde) when compared with the CTRL group (excipient). Three months after the fifth treatment, the increase in dermal thickness (%) was, respectively, 5.27 versus 1.13 for the forehead and 10.54 versus 3.57 for the neck. The difference between groups was statistically significant in favor of the retinaldehyde group for the forehead (p<0.05) and of limited significance for the neck (p=0.08). CONCLUSION: When considering the reduced number of patients in each group, the statistical analysis demonstrates an evident advantage of using retinaldehyde versus excipient. This study demonstrates that irradiation with a 1540 nm Er:glass laser can be potentiated with concomitant daily topical application of 0.05% retinaldehyde.

A retrospective study of the effect of long-term topical application of retinaldehyde (0.05%) on the development of actinic keratosis.

BACKGROUND: The role of topical retinoids on photocarcinogenesis is still unclear. Retinaldehyde is a natural metabolite of vitamin A used as a cosmetic product. Its effect on actinic keratoses has not been studied to date. OBJECTIVE: To study the incidence of actinic keratoses during long-term application of retinaldehyde in order to evaluate a possible chemoprophylactic effect. METHODS: We conducted a retrospective study on 61 patients who had applied retinaldehyde on photoexposed body areas for a period ranging from 6 to 142 months. We counted the total number of actinic keratoses and cutaneous tumors that appeared over the time of exposure to retinaldehyde. RESULTS: The epidemiological characteristics of actinic keratoses were not modified by the application of retinaldehyde. Irregular application as compared to regular application of retinaldehyde was not associated with a change in the risk of actinic keratoses, suggesting that continuous use is not associated per se with a higher risk of actinic keratoses. CONCLUSION: With the statistical power limitation of this study, retinaldehyde applied alone does not appear to have prophylactic effects on the development of actinic keratoses. The design adopted is feasible to study the safety of cosmetic products applied for a long period of time.

Topical retinaldehyde treatment in oral lichen planus and leukoplakia.

The aim of this exploratory study was to assess the efficacy of a natural metabolite of vitamin A, retinaldehyde 0.1%, vehicled in a gel in 17 patients with oral lichen planus and in 13 patients with oral leukoplakia, twice daily for 2 months. Our investigation was clinical, histological, immunohistochemical through the expression of markers of cell terminal differentiation and biochemical by using two-dimensional gel electrophoresis of cytokeratins (CK). In addition, the activity of retinaldehyde was studied ex vivo on surviving buccal mucosa. Retinaldehyde gel 0.1% showed good clinical efficacy, resulting in 6% disappearance and 82% improvement of the lesions in lichen planus and 17% disappearance and 75% improvement in leukoplakia. This was confirmed with immunohistochemistry, which revealed down-regulation of filaggrin and CK-10 as markers of terminal differentiation in both diseases. The effects of retinaldehyde in these two diseases were further demonstrated in the ex vivo surviving mucosal model, resulting in histological disappearance of keratinization in 80% of the lichen planus fragments and 40% of the leukoplakia fragments, associated with down-regulation of filaggrin and CK-10.

Retinaldehyde alleviates rosacea.

BACKGROUND: Anecdotal observations suggest that retinoic acid may be effective in mild rosacea. AIM: Our aim was to investigate, by an exploratory clinical and instrumental study, the effects of a topical formulation with the retinoic acid precursor retinaldehyde, in patients with vascular signs of facial rosacea. METHODS: Female patients were treated with a 0.05% retinaldehyde cream that was applied once daily for 6 months. Clinical assessments of persistent erythema and telangiectasia were performed every month, using a 4-point severity score (absent to severe). The clinical response for each parameter was defined as a decrease of at least 1 grade in the severity score. In addition, erythema was further evaluated by measurement of the a* parameter, using a spectrophotometer on lesional and nonlesional areas. RESULTS: A total of 23 women comprised the study population. At baseline, 10 patients had diffuse erythema, 3 patients had isolated telangiectasia and 10 patients had both. During retinaldehyde treatment, a clinical response was revealed in about 75% of the patients with erythema, after 5 months (p < 0.05). Similarly, isolated telangiectasia responded to retinaldehyde, although to a lesser extent and after a longer period of treatment (46% responders after 6 months, nonsignificant). Using the spectrophotometer, the a* parameter diminished in patients with erythema by about 15%, after 2 months of treatment (p = 0.001). CONCLUSION: This study indicates that retinaldehyde has beneficial effects on the vascular component of rosacea.

[Dynamics of vitamin A metabolism in the blood and semen of karakul ram sires]. / Dinamika obmena vitamina A v krovi i semeni baranov-proizvoditelei karakul'skoi porody.

Dynamics of vitamin A turnover in the blood and semen of astrakhan ram-sires was being studied for determining the ways of its transport to mature sperms. By means of high pressure liquid chromatography it was found that concentrations of retinol in the blood and retinyl palmitate in the semen of rams, suffering from hypovitaminosis A, rose simultaneously during the first 24 hours after feeding the animals with labelled retinol. According to the data on the specific activity of labelled vitamin A in the blood and semen a significant portion of the vitamin was transfered into the semen from the blood together with the secretions of epididymis and/or another sexual glands. The role of vitamin A in epididymal sperm maturation is discussed. A more prolonged increase of vitamin A levels in the blood and semen of the animals under study was achieved after double feeding of each animal with 60 mg of vitamin A.