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Article ; Online: Toward low-cost gene therapy: mRNA-based therapeutics for treatment of inherited retinal diseases.

Antas, Pedro / Carvalho, Cláudia / Cabral-Teixeira, Joaquim / de Lemos, Luísa / Seabra, Miguel C

2023 Volume 30, Issue 2, Page(s) 136–146

Abstract: Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. Gene therapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. Nevertheless, the associated ... ...

Abstract	Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. Gene therapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. Nevertheless, the associated costs impede widespread access, particularly in low-to-middle income countries. The primary challenge remains: how can we make these therapies globally affordable? Leveraging advancements in mRNA therapies might offer a more economically viable alternative. Furthermore, transitioning to nonviral delivery systems could provide a dual benefit of reduced costs and increased scalability. Relevant stakeholders must collaboratively devise and implement a research agenda to realize the potential of mRNA strategies in equitable access to treatments to prevent vision loss.
MeSH term(s)	Humans ; RNA, Messenger/genetics ; RNA, Messenger/therapeutic use ; Retinal Diseases/genetics ; Retinal Diseases/therapy ; Genetic Therapy/methods ; Mutation
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2023-12-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2036490-8
ISSN	1471-499X ; 1471-4914
ISSN (online)	1471-499X
ISSN	1471-4914
DOI	10.1016/j.molmed.2023.11.009
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Article ; Online: Melanin Transfer in the Epidermis: The Pursuit of Skin Pigmentation Control Mechanisms.

Moreiras, Hugo / Seabra, Miguel C / Barral, Duarte C

International journal of molecular sciences

2021 Volume 22, Issue 9

Abstract: The mechanisms by which the pigment melanin is transferred from melanocytes and processed within keratinocytes to achieve skin pigmentation remain ill-characterized. Nevertheless, several models have emerged in the past decades to explain the transfer ... ...

Abstract	The mechanisms by which the pigment melanin is transferred from melanocytes and processed within keratinocytes to achieve skin pigmentation remain ill-characterized. Nevertheless, several models have emerged in the past decades to explain the transfer process. Here, we review the proposed models for melanin transfer in the skin epidermis, the available evidence supporting each one, and the recent observations in favor of the exo/phagocytosis and shed vesicles models. In order to reconcile the transfer models, we propose that different mechanisms could co-exist to sustain skin pigmentation under different conditions. We also discuss the limited knowledge about melanin processing within keratinocytes. Finally, we pinpoint new questions that ought to be addressed to solve the long-lasting quest for the understanding of how basal skin pigmentation is controlled. This knowledge will allow the emergence of new strategies to treat pigmentary disorders that cause a significant socio-economic burden to patients and healthcare systems worldwide and could also have relevant cosmetic applications.
MeSH term(s)	Animals ; Epidermis/metabolism ; Humans ; Keratinocytes/metabolism ; Melanins/metabolism ; Melanocytes/metabolism ; Skin Pigmentation
Chemical Substances	Melanins
Language	English
Publishing date	2021-04-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22094466
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Article ; Online: Melanin Transfer in the Epidermis

Hugo Moreiras / Miguel C. Seabra / Duarte C. Barral

International Journal of Molecular Sciences, Vol 22, Iss 4466, p

The Pursuit of Skin Pigmentation Control Mechanisms

2021 Volume 4466

Abstract	The mechanisms by which the pigment melanin is transferred from melanocytes and processed within keratinocytes to achieve skin pigmentation remain ill-characterized. Nevertheless, several models have emerged in the past decades to explain the transfer process. Here, we review the proposed models for melanin transfer in the skin epidermis, the available evidence supporting each one, and the recent observations in favor of the exo/phagocytosis and shed vesicles models. In order to reconcile the transfer models, we propose that different mechanisms could co-exist to sustain skin pigmentation under different conditions. We also discuss the limited knowledge about melanin processing within keratinocytes. Finally, we pinpoint new questions that ought to be addressed to solve the long-lasting quest for the understanding of how basal skin pigmentation is controlled. This knowledge will allow the emergence of new strategies to treat pigmentary disorders that cause a significant socio-economic burden to patients and healthcare systems worldwide and could also have relevant cosmetic applications.
Keywords	melanin ; melanosome ; melanocore ; melanocyte ; keratinocyte ; skin pigmentation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Retinal Progression Biomarkers of Early and Intermediate Age-Related Macular Degeneration

Rita Flores / Ângela Carneiro / Sandra Tenreiro / Miguel C. Seabra

Life, Vol 12, Iss 36, p

2022 Volume 36

Abstract: Early and intermediate AMD patients represent a heterogeneous population with an important but variable risk of progression to more advanced stages of the disease. The five-year progression from early and intermediate AMD to late disease is known to ... ...

Abstract	Early and intermediate AMD patients represent a heterogeneous population with an important but variable risk of progression to more advanced stages of the disease. The five-year progression from early and intermediate AMD to late disease is known to range from 0.4% to 53%. This wide variation explains the particular interest in searching predictive AMD biomarkers. Clinical parameters such as drusen size, presence of pigmentary abnormalities, and fellow eye status were, traditionally, the more important predictive elements. Multimodal retinal assessment (Color Fundus Photography, Optical Coherence Tomography, Optical Coherence Angiography and Fundus Autofluorescence) is providing new and accurate image biomarkers, useful in research and in daily practice. If individual progression risk could be anticipated, then management plans should be adapted accordingly, considering follow-up intervals and therapeutic interventions. Here, we reviewed the most important image progression biomarkers of early and intermediate AMD with relevant interest in clinical practice.
Keywords	age related macular degeneration (AMD) ; drusen ; color fundus photography ; optical coherence tomography ; OCT-angiography ; progression biomarkers ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Age-Related Macular Degeneration: Pathophysiology, Management, and Future Perspectives.

Flores, Rita / Carneiro, Ângela / Vieira, Miguel / Tenreiro, Sandra / Seabra, Miguel C

Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde

2021 Volume 244, Issue 6, Page(s) 495–511

Abstract: Among older adults, age-related macular degeneration (AMD) is a prevalent disabling condition that begins as subtle visual disturbances and can progress to permanent loss of central vision. In its late neovascular form, AMD is treatable with inhibitors ... ...

Abstract	Among older adults, age-related macular degeneration (AMD) is a prevalent disabling condition that begins as subtle visual disturbances and can progress to permanent loss of central vision. In its late neovascular form, AMD is treatable with inhibitors of vascular endothelial growth factor, the key driver of exudative disease. In the atrophic form, treatment remains elusive. This review addresses the natural history of AMD - through early, intermediate, and advanced disease stages - and concentrates on diagnosis and risk stratification, deficiencies of current treatments, and the promising findings of emerging therapies.
MeSH term(s)	Aged ; Blindness ; Humans ; Macular Degeneration/diagnosis ; Macular Degeneration/therapy ; Vascular Endothelial Growth Factor A/antagonists & inhibitors
Chemical Substances	Vascular Endothelial Growth Factor A
Language	English
Publishing date	2021-06-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	209735-7
ISSN	1423-0267 ; 0030-3755
ISSN (online)	1423-0267
ISSN	0030-3755
DOI	10.1159/000517520
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Article ; Online: Deacidification of endolysosomes by neuronal aging drives synapse loss.

Burrinha, Tatiana / Cunha, César / Hall, Michael J / Lopes-da-Silva, Mafalda / Seabra, Miguel C / Guimas Almeida, Cláudia

Traffic (Copenhagen, Denmark)

2023 Volume 24, Issue 8, Page(s) 334–354

Abstract: Previously, we found that age-dependent accumulation of beta-amyloid is not sufficient to cause synaptic decline. Late-endocytic organelles (LEOs) may be driving synaptic decline as lysosomes (Lys) are a target of cellular aging and relevant for synapses. ...

Abstract	Previously, we found that age-dependent accumulation of beta-amyloid is not sufficient to cause synaptic decline. Late-endocytic organelles (LEOs) may be driving synaptic decline as lysosomes (Lys) are a target of cellular aging and relevant for synapses. We found that LAMP1-positive LEOs increased in size and number and accumulated near synapses in aged neurons and brains. LEOs' distal accumulation might relate to the increased anterograde movement in aged neurons. Dissecting the LEOs, we found that late-endosomes accumulated while there are fewer terminal Lys in aged neurites, but not in the cell body. The most abundant LEOs were degradative Lys or endolysosomes (ELys), especially in neurites. ELys activity was reduced because of acidification defects, supported by the reduction in v-ATPase subunit V0a1 with aging. Increasing the acidification of aged ELys recovered degradation and reverted synaptic decline, while alkalinization or v-ATPase inhibition, mimicked age-dependent Lys and synapse dysfunction. We identify ELys deacidification as a neuronal mechanism of age-dependent synapse loss. Our findings suggest that future therapeutic strategies to address endolysosomal defects might be able to delay age-related synaptic decline.
MeSH term(s)	Neurons/metabolism ; Synapses ; Endosomes/metabolism ; Lysosomes/metabolism ; Adenosine Triphosphatases/metabolism
Chemical Substances	Adenosine Triphosphatases (EC 3.6.1.-)
Language	English
Publishing date	2023-05-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1483852-7
ISSN	1600-0854 ; 1398-9219
ISSN (online)	1600-0854
ISSN	1398-9219
DOI	10.1111/tra.12889
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Article: Retinal Progression Biomarkers of Early and Intermediate Age-Related Macular Degeneration.

Flores, Rita / Carneiro, Ângela / Tenreiro, Sandra / Seabra, Miguel C

Life (Basel, Switzerland)

2021 Volume 12, Issue 1

Abstract	Early and intermediate AMD patients represent a heterogeneous population with an important but variable risk of progression to more advanced stages of the disease. The five-year progression from early and intermediate AMD to late disease is known to range from 0.4% to 53%. This wide variation explains the particular interest in searching predictive AMD biomarkers. Clinical parameters such as drusen size, presence of pigmentary abnormalities, and fellow eye status were, traditionally, the more important predictive elements. Multimodal retinal assessment (Color Fundus Photography, Optical Coherence Tomography, Optical Coherence Angiography and Fundus Autofluorescence) is providing new and accurate image biomarkers, useful in research and in daily practice. If individual progression risk could be anticipated, then management plans should be adapted accordingly, considering follow-up intervals and therapeutic interventions. Here, we reviewed the most important image progression biomarkers of early and intermediate AMD with relevant interest in clinical practice.
Language	English
Publishing date	2021-12-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life12010036
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Article ; Online: Melanin's Journey from Melanocytes to Keratinocytes: Uncovering the Molecular Mechanisms of Melanin Transfer and Processing.

Bento-Lopes, Liliana / Cabaço, Luís C / Charneca, João / Neto, Matilde V / Seabra, Miguel C / Barral, Duarte C

International journal of molecular sciences

2023 Volume 24, Issue 14

Abstract: Skin pigmentation ensures efficient photoprotection and relies on the pigment melanin, which is produced by epidermal melanocytes and transferred to surrounding keratinocytes. While the molecular mechanisms of melanin synthesis and transport in ... ...

Abstract	Skin pigmentation ensures efficient photoprotection and relies on the pigment melanin, which is produced by epidermal melanocytes and transferred to surrounding keratinocytes. While the molecular mechanisms of melanin synthesis and transport in melanocytes are now well characterized, much less is known about melanin transfer and processing within keratinocytes. Over the past few decades, distinct models have been proposed to explain how melanin transfer occurs at the cellular and molecular levels. However, this remains a debated topic, as up to four different models have been proposed, with evidence presented supporting each. Here, we review the current knowledge on the regulation of melanin exocytosis, internalization, processing, and polarization. Regarding the different transfer models, we discuss how these might co-exist to regulate skin pigmentation under different conditions, i.e., constitutive and facultative skin pigmentation or physiological and pathological conditions. Moreover, we discuss recent evidence that sheds light on the regulation of melanin exocytosis by melanocytes and internalization by keratinocytes, as well as how melanin is stored within these cells in a compartment that we propose be named the melanokerasome. Finally, we review the state of the art on the molecular mechanisms that lead to melanokerasome positioning above the nuclei of keratinocytes, forming supranuclear caps that shield the nuclear DNA from UV radiation. Thus, we provide a comprehensive overview of the current knowledge on the molecular mechanisms regulating skin pigmentation, from melanin exocytosis by melanocytes and internalization by keratinocytes to processing and polarization within keratinocytes. A better knowledge of these molecular mechanisms will clarify long-lasting questions in the field that are crucial for the understanding of skin pigmentation and can shed light on fundamental aspects of organelle biology. Ultimately, this knowledge can lead to novel therapeutic strategies to treat hypo- or hyper-pigmentation disorders, which have a high socio-economic burden on patients and healthcare systems worldwide, as well as cosmetic applications.
MeSH term(s)	Humans ; Melanins ; Melanocytes/physiology ; Keratinocytes/physiology ; Epidermis ; Skin Pigmentation ; Melanosomes
Chemical Substances	Melanins
Language	English
Publishing date	2023-07-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms241411289
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Article ; Online: Identifying Imaging Predictors of Intermediate Age-Related Macular Degeneration Progression.

Flores, Rita / Fradinho, Ana C / Pereira, Rita Serras / Mendes, Jorge M / Seabra, Miguel C / Tenreiro, Sandra / Carneiro, Ângela

Translational vision science & technology

2023 Volume 12, Issue 7, Page(s) 22

Abstract: Purpose: Intermediate age-related macular degeneration (iAMD) is a risk factor for progression to advanced stages, but rates of progression vary between individuals. Predicting individual risk is advantageous for programing timely and effective ... ...

Abstract	Purpose: Intermediate age-related macular degeneration (iAMD) is a risk factor for progression to advanced stages, but rates of progression vary between individuals. Predicting individual risk is advantageous for programing timely and effective treatment and for patient stratification into future clinical trials. Methods: We conducted a prospective and noninterventional study following patients with iAMD for 24 months. Optical coherence tomography parameters related with drusen, hyper-reflective foci (HRF), presence of incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) and ellipsoid zone (EZ) status were explored at the baseline. Patients were reclassified at the end of the follow-up period and divided according to their progression. A risk prediction model for progression to late AMD was developed. Results: A total of 135 patients were enrolled in the study and 30.4% developed late disease. A multivariate logistic regression model was created using those optical coherence tomography parameters, further optimized by backward feature elimination. Parameters offering the best fit in prediction progression were presence of iRORA, EZ status, drusen area and presence of HRF. iRORA is the feature that provides a higher probability of developing late AMD (odds ratio, 12.91; P = 0.000), followed by EZ disruption status (odds ratio, 3.54; P = 0.0018). The area under the receiver operating characteristic curve calculated for the testing set was 0.77 (95% confidence interval, 0.56-0.98). Conclusions: The combination of iRORA and EZ disruption constitute a high risk of progression to complete RORA within 2 years. Translational relevance: We propose a practical and useful model to help clinicians in their daily practice in predicting individual progression to advanced AMD.
MeSH term(s)	Humans ; Prospective Studies ; Macular Degeneration ; Tomography, Optical Coherence
Language	English
Publishing date	2023-07-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2674602-5
ISSN	2164-2591 ; 2164-2591
ISSN (online)	2164-2591
ISSN	2164-2591
DOI	10.1167/tvst.12.7.22
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Article ; Online: Impaired Lysosome Reformation in Chloroquine-Treated Retinal Pigment Epithelial Cells.

Cardoso, M Helena / Hall, Michael J / Burgoyne, Thomas / Fale, Pedro / Storm, Tina / Escrevente, Cristina / Antas, Pedro / Seabra, Miguel C / Futter, Clare E

Investigative ophthalmology & visual science

2023 Volume 64, Issue 11, Page(s) 10

Abstract: Purpose: To model the in vivo effects of chloroquine on the retinal pigment epithelium in experimentally tractable cell culture systems and determine the effects of mild chloroquine treatment on lysosome function and turnover.: Methods: Effects of ... ...

Abstract	Purpose: To model the in vivo effects of chloroquine on the retinal pigment epithelium in experimentally tractable cell culture systems and determine the effects of mild chloroquine treatment on lysosome function and turnover. Methods: Effects of low-dose chloroquine treatment on lysosomal function and accessibility to newly endocytosed cargo were investigated in primary and embryonic stem cell-derived RPE cells and ARPE19 cells using fluorescence and electron microscopy of fluorescent and gold-labeled probes. Lysosomal protein expression and accumulation were measured by quantitative PCR and Western blotting. Results: Initial chloroquine-induced lysosome neutralization was followed by partial recovery, lysosomal expansion, and accumulation of undegraded endocytic, phagocytic, and autophagic cargo and inhibition of cathepsin D processing. Accumulation of enlarged lysosomes was accompanied by a gradual loss of accessibility of these structures to the endocytic pathway, implying impaired lysosome reformation. Chloroquine-induced accumulation of pro-cathepsin D, as well as the lysosomal membrane protein, LAMP1, was reproduced by treatment with protease inhibitors and preceded changes in lysosomal gene expression. Conclusions: Low-dose chloroquine treatment inhibits lysosome reformation, causing a gradual depletion of lysosomes able to interact with cargo-carrying vacuoles and degrade their content. The resulting accumulation of newly synthesized pro-cathepsin D and LAMP1 reflects inhibition of normal turnover of lysosomal constituents and possibly lysosomes themselves. A better understanding of the mechanisms underlying lysosome reformation may reveal new targets for the treatment of chloroquine-induced retinopathy.
MeSH term(s)	Humans ; Chloroquine/toxicity ; Lysosomes/metabolism ; Phagocytosis ; Autophagy/physiology ; Retinal Diseases/metabolism ; Epithelial Cells/metabolism ; Retinal Pigments/metabolism
Chemical Substances	Chloroquine (886U3H6UFF) ; Retinal Pigments
Language	English
Publishing date	2023-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.64.11.10
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