Sucha degeneracja plamki żółtej – Patofizjologia i mechanizm

Sucha degeneracja plamki żółtej
Patofizjologia i mechanizm

Sucha degeneracja plamki żółtej (AMD) to przewlekła, postępująca choroba degeneracyjna plamki żółtej, dotykająca ponad 90% pacjentów z AMD, będąca główną przyczyną utraty centralnego widzenia u osób powyżej 60. roku życia. Patogeneza obejmuje złożone interakcje genetyczno-środowiskowe, prowadzące do degeneracji nabłonka barwnikowego siatkówki (RPE), fotoreceptorów i naczyniówki. Kluczowe zmiany patologiczne to pogrubienie błony Brucha, gromadzenie druz (złogów lipidowo-białkowych), zaburzenia RPE oraz zanik geograficzny (GA). Dysregulacja układu dopełniacza, zwłaszcza drogi alternatywnej, odgrywa centralną rolę w patogenezie, potwierdzoną obecnością białek dopełniacza w druzach oraz polimorfizmami genów CFH, CFB i C3. Stres oksydacyjny i mitochondrialna dysfunkcja RPE, wraz z akumulacją lipofuscyny i toksycznego fluoroforu A2E, nasilają uszkodzenia komórkowe. Dysfunkcja autofagii i aktywacja inflamasomu NLRP3 w RPE dodatkowo przyczyniają się do przewlekłego stanu zapalnego i progresji choroby.

Patogeneza suchej degeneracji plamki żółtej

Zmiany strukturalne w patogenezie suchej AMD
Rola procesów zapalnych i układu dopełniacza
Stres oksydacyjny i dysfunkcja mitochondriów
<a href="#rola-lipofuscyny-i-a2e”>Rola lipofuscyny i A2E
Autofagia i jej zaburzenia
Czynniki genetyczne w patogenezie suchej AMD
Mechanizmy śmierci komórek w suchej AMD

Niewłaściwa aktywacja układu dopełniacza

Rola inflamasomów w patogenezie suchej AMD

Podsumowanie patogenezy suchej AMD

Kolejne rozdziały

Patogeneza suchej degeneracji plamki żółtej

Sucha degeneracja plamki żółtej (AMD – Age-related Macular Degeneration) stanowi najczęstszą postać AMD, dotykając ponad 90% pacjentów z tym schorzeniem. Jest to postępująca choroba degeneracyjna plamki żółtej, która prowadzi do utraty centralnego widzenia i stanowi główną przyczynę ślepoty w krajach rozwiniętych wśród osób powyżej 60. roku życia. Patogeneza suchej AMD jest złożona i wieloczynnikowa, obejmując interakcje genetyczno-środowiskowe oraz liczne procesy biochemiczne i komórkowe, które prowadzą do degeneracji nabłonka barwnikowego siatkówki (RPE), fotoreceptorów i naczyniówki.¹²³

Zmiany strukturalne w patogenezie suchej AMD

Podstawowe zmiany patologiczne w suchej AMD obejmują pogrubienie błony Brucha, gromadzenie się druz, zaburzenia nabłonka barwnikowego siatkówki oraz stopniowy zanik geograficzny. Błona Brucha ulega pogrubieniu wskutek akumulacji lipidów i białek, co prowadzi do tworzenia złogów pod nabłonkiem barwnikowym siatkówki. Te złogi mogą występować jako odrębne akumulacje, zwane druzami, które mogą być twarde lub miękkie, albo jako ciągłe nagromadzenia.¹²

Druzy są uznawane za charakterystyczną cechę wczesnych stadiów AMD, widoczną klinicznie jako żółtawe plamki w obszarach przyległych do dołka środkowego lub plamki. Histopatologicznie druzy reprezentują złogi materiału zewnątrzkomórkowego między nabłonkiem barwnikowym siatkówki a błoną Brucha wzdłuż interfejsu naczyniówkowo-siatkówkowego.¹ Chociaż dokładna rola druz w patogenezie AMD nie została w pełni wyjaśniona, wiadomo, że stanowią one kluczowe zmiany w AMD. Nie jest jasne, czy druzy są pierwotną przyczyną degeneracji RPE w AMD, jednak ostatecznie wpływają na zdrowie RPE ze względu na upośledzony transport przez błonę Brucha.¹

Z czasem dochodzi do zaniku RPE i fotoreceptorów w określonych obszarach, co prowadzi do zaniku geograficznego (GA) – zaawansowanej formy suchej AMD. Zmiany te są poprzedzone (lub współwystępują w niektórych przypadkach) obecnością żółtych pozakomórkowych złogów przylegających do podstawowej powierzchni RPE, zwanych druzami.¹²

Rola procesów zapalnych i układu dopełniacza

Istotnym elementem patogenezy suchej AMD jest przewlekły proces zapalny, szczególnie związany z dysregulacją układu dopełniacza. Identyfikacja polimorfizmów w genach kodujących czynnik H dopełniacza (CFH), czynnik B i C3, które zwiększają ryzyko rozwoju AMD, potwierdziła wcześniejsze badania patobiologiczne, które doprowadziły do identyfikacji licznych białek dopełniacza w druzach.¹²

Dysregulacja kaskady dopełniacza, szczególnie drogi alternatywnej, jest obecnie uważana za krytyczny predysponujący krok w rozwoju AMD. Chociaż dokładne wydarzenie(a) wyzwalające, które prowokuje patologię RPE i naczyniówki, pozostają nieznane, jasne jest, że głównym konsekwencją jest odkładanie i sekwestracja komórkowych i bezkomórkowych resztek w przestrzeni pod RPE, co prowadzi do tworzenia druz.¹²

Obecnie podejrzewa się, że w AMD dochodzi do ubocznego uszkodzenia poprzez dysregulację dopełniacza, gdzie pacjenci z niewystarczającą aktywnością modulującą drogę alternatywną doświadczają następnie ataku dopełniacza, ubocznego uszkodzenia sąsiednich komórek, ciągłego tworzenia druz i innych złogów pod RPE, a ostatecznie utraty widzenia.¹²³

W AMD uważa się, że wczesne „wydarzenie zalążkowe”, takie jak obszar zaniku nabłonka barwnikowego siatkówki z resztkami komórkowymi, indukuje aktywację wrodzonego układu odpornościowego na poziomie kompleksu RPE-naczyniówka-błona Brucha. Następnie atak dopełniacza (aktywacja kompleksu atakującego błonę) prowadzi do ubocznego uszkodzenia tkanki siatkówki.¹

Stres oksydacyjny i dysfunkcja mitochondriów

Stres oksydacyjny jest ważnym czynnikiem w patogenezie suchej AMD. Siatkówka jest szczególnie podatna na uszkodzenia oksydacyjne ze względu na wysokie zużycie tlenu i ekspozycję na światło, co prowadzi do akumulacji takich uszkodzeń i skutkuje dysfunkcją komórkową i śmiercią.¹²

Mitochondrialna dysfunkcja została wskazana jako istotny czynnik w etiologii suchej AMD. Dysmorfologia mitochondrialna obserwowana w RPE w oczach z AMD jest zgodna z poważną dysfunkcją, a mitochondrialny DNA z tych oczu wykazuje zwiększone uszkodzenia oksydacyjne.¹²

W suchej AMD mitochondria RPE mają zmniejszoną masę, są morfologicznie nieprawidłowe, a uszkodzenia mitochondrialnego DNA zwiększają się wraz z nasileniem choroby. Dysfunkcyjne mitochondria w RPE w AMD mogą prowadzić do zwiększonej odpowiedzi na stres oksydacyjny i przesunięcia z fosforylacji oksydacyjnej do glikolitycznej produkcji ATP.¹²³

Badania wskazują, że narażenie na hydrochinon powoduje ostrą i przewlekłą dysfunkcję mitochondrialną, prowadzącą do biochemicznych i komórkowych zmian zgodnych z suchą AMD. Związek MTP-131 (Ocuvia), opracowywany przez Stealth BioTherapeutics, jest badany jako potencjalny lek chroniący mitochondria w leczeniu suchej AMD.¹²

lipofuscyny-i-a2e”>Rola lipofuscyny i A2E

Lipofuscyna to grupa autofluorescencyjnych agregatów lipidowo-białkowych obecnych w tkankach nieneuronalnych i neuronalnych. Z wiekiem lipofuscyna gromadzi się w kompartmencie lizosomalnym postmitotycznych komórek RPE z powodu niepełnej degradacji zewnętrznych segmentów fotoreceptorów.¹²

A2E, fluorofor obecny w lipofuscynie, jest głównym fotouczulającym chromoforem w lipofuscynie, który powoduje produkcję reaktywnych form tlenu (ROS). A2E może zmieniać się w A2E-epoksyd pod wpływem niebieskiego światła, a jednocześnie mogą być syntetyzowane liczne ROS, takie jak H₂O₂, O₂⁻ i OH·, które mogą rozpoczynać oksydację i niszczenie RPE.¹²

Produkcja jednego z takich fluoroforów lipofuscyny, A2E, jest markerem dysfunkcji RPE i jest znacząco związana z patogenezą AMD. Zgromadzone druzy nie tylko wywołują ślepotę w obszarze centralnym, ale również stymulują zapalenie w RPE, a nasilenie odpowiedzi zapalnej jest czynnikiem wyzwalającym wystąpienie AMD.¹²

Autofagia i jej zaburzenia

Autofagia jest procesem degradacji zapośredniczowanym przez lizosomy dla niepotrzebnych lub uszkodzonych składników komórkowych w celu dostarczenia komórce energii i utrzymania homeostazy. Ostatnio wykazano, że dysregulowana autofagia w RPE zwiększa podatność na stres oksydacyjny i AMD.¹

Dysregulacja autofagii może prowadzić do dysfunkcji komórkowej. AMD ma cechy degeneracyjne, w tym złogi białkowe, a w niektórych przypadkach cechy proliferacyjne, jak w mokrej AMD; dlatego nie ma konsensusu co do tego, czy inhibitory czy aktywatory autofagii byłyby korzystne w terapii AMD i jak powinny być stosowane w przypadku różnych fenotypów AMD.¹²

Dysfunkcyjna autofagia w RPE może prowadzić do dezintegracji mitochondrialnej poprzez wpływ na stosunek podziału/fuzji mitochondriów, który jest kluczowy dla utrzymania funkcjonalnych mitochondriów. Badania sugerują, że upośledzona dynamika autofagii w RPE przyczynia się do patofizjologii AMD.¹

Rola czynnika DICER1

Aktywność enzymu DICER1 jest wystarczająco szeroka, aby być atrakcyjnym kandydatem jako dyrygent zdrowia i homeostazy siatkówki. Skumulowane obciążenie RPE może, ale nie musi, zbiegać się do pojedynczej ścieżki, która determinuje żywotność komórek RPE.¹

RNA Alu, które gromadzą się w niedoborze DICER1, są transkrybowane z sekwencji DNA Alu w genomie jądrowym. Szkodliwy wpływ sekwencji Alu jest często przypisywany pojedynczemu zdarzeniu retrotranspozycji; na przykład sekwencja Alu może wstawić się do krytycznego genu, zakłócając w ten sposób funkcję genu.¹

Nowe badania wskazują, że bezpośrednia toksyczność RNA, a konkretnie zapalenie pośredniczone przez RNA Alu, może odgrywać znaczącą rolę w patogenezie zaniku geograficznego.¹

Czynniki genetyczne w patogenezie suchej AMD

Badania genetyczne i genomiczne przyczyniły się znacząco do zrozumienia patogenezy AMD. AMD jest obecnie jedną z najlepiej zrozumianych złożonych, wieloczynnikowych chorób.¹²

Trzy loci, w których znaleziono warianty genów, to: Czynnik H Dopełniacza (CFH) na chromosomie 1 w lokalizacji 1q31.3, HTRA serynowa peptydaza 1/Podatność 2 na Makulopatię Związaną z Wiekiem (HTRA1/ARMS2) na chromosomie 10 w lokalizacji 10q26, Czynnik B Dopełniacza/Składnik Dopełniacza 2 (CFB/CC2) na chromosomie 6 w 6p21.3.¹²

W 2005 roku cztery oddzielne grupy doniosły, że powszechna wariacja w genie CFH (czynnik H dopełniacza) zwiększa podatność na suchą AMD. Polimorfizmy w wielu innych genach również zostały powiązane ze zwiększonym ryzykiem rozwoju AMD, w tym geny zaangażowane w kaskadę dopełniacza, ARMS2, ABCA4 i HTRA1.¹²

Obecność wariantów genetycznych zwiększających ryzyko AMD silnie sugeruje udział drogi alternatywnej dopełniacza jako kluczowego mechanizmu w patogenezie AMD. Polimorficzne warianty w genach kodujących czynnik H dopełniacza, składnik dopełniacza 3 i podatność na makulopatię związaną z wiekiem 2 wykazano, że znacząco zwiększają ryzyko rozwoju AMD. Analiza histologiczna pacjentów z AMD ujawniła również obecność składnika dopełniacza 5, a także końcowego kompleksu atakującego błonę, C5b-9, w druzach.¹²

Mechanizmy śmierci komórek w suchej AMD

Śmierć komórek fotoreceptorów jest podstawą trwałego pogorszenia widzenia w suchej AMD. Dlatego identyfikacja mechanizmów zaangażowanych w śmierć fotoreceptorów jest kluczowa dla opracowania nowych metod leczenia zapobiegających trwałej utracie widzenia.¹²

Mechanizmy śmierci komórek RPE mogą różnić się od mechanizmów śmierci fotoreceptorów. Ponieważ ścieżki śmierci komórkowej są redundantne i komplementarne, terapie kombinowane blokujące zarówno apoptozę, jak i nekrozę mogą być skuteczne w suchej AMD.¹

Niektóre badania nakreśliły ścieżkę molekularną prowadzącą do zaniku geograficznego i utraty widzenia. Ta ścieżka wskazuje, że śmierć RPE prowadzi do wtórnej utraty fotoreceptorów i w konsekwencji do utraty widzenia z czasem.¹

Niewłaściwa aktywacja układu dopełniacza

Niewłaściwa aktywacja układu dopełniacza, głównie drogi alternatywnej, pośredniczy w przewlekłej autologicznej patofizjologicznej parainflamacji w suchej i wysiękowej AMD. Badania genetyczne wskazały na rolę zapalenia w AMD. Dysregulacja aktywności dopełniacza może prowadzić do uszkodzenia tkanek i jest centralnym elementem patogenezy suchej AMD.¹²³

Aktywacja układu dopełniacza skutkuje uszkodzeniem komórkowym, które jest centralnym czynnikiem w patogenezie suchej i mokrej formy AMD, co jest potwierdzone obecnością wielu białek układu dopełniacza w druzach u pacjentów z AMD.¹²

Dysregulacja układu dopełniacza w suchej AMD i zaniku geograficznym została dodatkowo potwierdzona przez dowody wariantów genetycznych charakteryzujących pacjentów z AMD, związanych z jego nieprawidłową regulacją w górę. Duże znaczenie aktywacji układu dopełniacza w patogenezie AMD i zaniku geograficznego skłoniło firmy do opracowania terapii ukierunkowanych na czynniki dopełniacza.¹²

W 2023 roku pegcetacoplan podawany do ciała szklistego i awacyncaptad pegol stały się dostępne w leczeniu zaawansowanej suchej AMD z powodu zaniku geograficznego. Te leki hamują szlak dopełniacza i mogą spowolnić progresję zaniku geograficznego.¹²

Rola inflamasomów w patogenezie suchej AMD

Aktywacja inflamasomu w RPE została po raz pierwszy zgłoszona w 2012 roku. Ostateczny mechanizm pozostaje do wyjaśnienia, ale w pierwotnych ludzkich komórkach nabłonka płuc MAC wyzwalał inflamasomy NLRP3 poprzez zwiększenie wewnątrzkomórkowego stężenia Ca²⁺ z następującą utratą mitochondrialnego potencjału błonowego.¹

Istnieje wiele innych sygnałów niebezpieczeństwa dla inflamasomów NLRP3 w RPE, np. akumulacja RNA Alu, pojawienie się końcowego produktu peroksydacji lipidów HNE (4-hydroksynonenal), a także obecność wewnątrzkomórkowych agregatów białkowych, której towarzyszy spadek efektywności autofagii. Chociaż RPE i zapalne komórki siatkówki mogą produkować zarówno cytokiny zależne od inflamasomu, uwalnianie cytokin może być skierowane albo na IL-1, albo na IL-18.¹²

Stres oksydacyjny jest ściśle związany z zapaleniem, a w szczególności A2E stymuluje zapalenie komórek RPE poprzez zwiększenie poziomu IL-1β za pośrednictwem inflamasomu NLRP3.¹

Podsumowanie patogenezy suchej AMD

Patogeneza suchej AMD jest złożonym procesem obejmującym wiele powiązanych ze sobą ścieżek, w tym stres oksydacyjny, dysfunkcję mitochondrialną, zapalenie, dysregulację układu dopełniacza, zaburzenia autofagii oraz czynniki genetyczne. Wszystkie te procesy przyczyniają się do postępującej degeneracji nabłonka barwnikowego siatkówki, fotoreceptorów i naczyniówki, co prowadzi do zaniku geograficznego i utraty centralnego widzenia.¹²

Zarbin podsumował swoją analizę patogenezy AMD w pięciu kolejnych krokach: (1) AMD obejmuje zmiany związane ze starzeniem się plus dodatkowe zmiany patologiczne (tj. AMD nie jest tylko zmianą związaną ze starzeniem się); (2) w starzeniu się i AMD stres oksydacyjny powoduje uszkodzenie RPE i, możliwe, naczyniówki; (3) w AMD (i być może w starzeniu się) uszkodzenie RPE i, możliwie, naczyniówki skutkuje przewlekłą odpowiedzią zapalną w obrębie błony Brucha i naczyniówki; (4) w AMD uszkodzenie RPE i, możliwie, naczyniówki oraz zapalenie prowadzą do tworzenia nieprawidłowej macierzy pozakomórkowej, co powoduje zmienioną dyfuzję składników odżywczych do siatkówki i RPE, możliwie przyspieszając dalsze uszkodzenia RPE i siatkówki; oraz (5) nieprawidłowa macierz pozakomórkowa skutkuje zmienionym zachowaniem RPE-naczyniówki, prowadzącym ostatecznie do atrofii siatkówki, RPE i naczyniówki i/lub wzrostu nowych naczyń naczyniówki.¹

Zrozumienie patogenezy suchej AMD jest kluczowe dla opracowania skutecznych terapii. Obecnie badane są różne strategie terapeutyczne, w tym leki przeciwutleniające, inhibitory kaskady dopełniacza, środki neuroprotekcyjne, inhibitory cyklu wzrokowego, terapia genowa i terapie oparte na komórkach.¹²

Badania przyszłych kierunków w badaniach nad suchą AMD powinny kłaść nacisk na podejścia biologii systemowej, które integrują dane omiczne, farmakologiczne i kliniczne w modele matematyczne, które mogą przewidywać wystąpienie i progresję choroby, identyfikować biomarkery, ustalać mechanizmy powodujące chorobę i monitorować odpowiedź na terapię.¹

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Materiały źródłowe

#1 Nonexudative (Dry) Age-Related Macular Degeneration (AMD): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1223154-overview
Nonexudative (dry) age-related macular degeneration (AMD or ARMD) accounts for more than 90% of patients diagnosed with AMD. […] AMD is associated with the presence of drusen, without visual loss early in the disease. However, the disease often slowly progresses over years to retinal atrophy and central retinal degeneration with associated loss of central vision. […] The early form of dry AMD is characterized by small to intermediate sized drusen, without significant vision loss. The intermediate form of dry AMD is associated with loss of retinal pigment epithelium (RPE) and the overlying retinal layers (atrophy), with loss of contrast sensitivity, loss of reading speed, and difficulty with adaptation to changing light conditions. The advanced, nonexudative form of AMD is characterized by the presence of atrophy that can be associated with severe central visual-field loss.
#1 Dry Age-Related Macular Degeneration: Mechanisms, Therapeutic Targets, and Imaging
https://pmc.ncbi.nlm.nih.gov/articles/PMC3864379/
The pathogenesis of early AMD is characterized by thickening of Bruch membrane (BrM) due to lipid and protein accumulation that lead to formation of sub-RPE deposits that occur as discrete accumulations, called drusen, which can be hard or soft, or as continuous accumulations. […] The role of drusen in the pathogenesis of AMD has not been clarified, although it has long been known that they constitute hallmark lesions of AMD. […] It is not known if drusen are the primary cause for the degeneration of RPE in AMD, but they do ultimately affect RPE health due to impaired transport across BrM. […] Thus, elimination of these soft drusen present as an obvious therapeutic target to slow or inhibit AMD progression. […] The identification of polymorphisms in genes coding for complement factor H (CFH), factor B, and C3, which confer greater risk for developing AMD, supported earlier pathobiologic investigations that led to the identification of numerous complement proteins in drusen.
#1 The Pathogenesis of Dry Age-related Macular Degeneration – Retina Today
https://retinatoday.com/articles/2011-apr/the-pathogenesis-of-dry-age-related-macular-degeneration
Clinical funduscopic examination showing yellow spots called drusen in the areas proximal to the fovea or macula is a diagnostic feature of dry AMD. Histopathologic features of dry AMD include atrophy and loss of retinal photoreceptors and retinal pigment epithelium (RPE), deposition of drusen between the RPE and Bruch membrane along the chorioretinal interphase, and accumulation of lipofuscin (A2E). […] Although the mouse retina lacks a macula, the vast amount of genetic and biologic manipulations available in the mouse provides researchers with multiple cost-efficient opportunities to dissect the various histologic and clinical manifestations of dry AMD and achieve interdisciplinary study of such a complex disease. […] For instance, many studies have shown that inflammatory processes are involved in the progression of disease, with the presence of acute-phase proteins, complement deposition, macrophage and microglial infiltration, and cytokine expression in affected tissue.
#1 Nonexudative (Dry) Age-Related Macular Degeneration (AMD): Practice Essentials, Background, Pathophysiology
https://emedicine.medscape.com/article/1223154-overview
Inappropriate activation of the complement system, a mainly alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD. […] In 2005, four separate groups reported that a common variation in the CFH (complement factor H) gene increased susceptibility to dry AMD. […] Some studies have delineated a molecular pathway leading to geographic atrophy and visual loss. This pathway indicates that RPE death leads to secondary photoreceptor loss and consequent visual loss over time.
#1 Dry Age-Related Macular Degeneration: Mechanisms, Therapeutic Targets, and Imaging
https://pmc.ncbi.nlm.nih.gov/articles/PMC3864379/
It is now apparent that dysregulation of the complement cascade, and of the alternative pathway in particular, is a critical predisposing step in AMD development. […] Although the precise triggering event(s) that provokes RPE-choroidal pathology are unknown, it is clear that a major consequence is the deposition and sequestration of cellular and acellular debris in the sub-RPE space that leads to drusen formation. […] Currently, the bystander damage through complement dysregulation is suspected in AMD, where those patients lacking sufficient alternative pathway-modulating activity have subsequently sustained complement attack, bystander injury to neighboring cells, continued formation of drusen and other sub-RPE deposits, and eventually vision loss. […] Dysregulation of autophagy can result in cellular dysfunction. AMD has degenerative characteristics including protein deposits, and in certain cases, proliferative characteristics as occurs in wet AMD; thus, there is no consensus as to whether autophagy inhibitors or activators would be beneficial in AMD therapy, and how they should be used for different phenotypes of AMD.
#1 Age-Related Macular Degeneration – EyeWiki
https://eyewiki.org/Age-Related_Macular_Degeneration
In AMD, it is believed that an early „seeding event,” such as an area of retinal pigment epithelium atrophy with cellular debris, induces innate immune system activation at the RPE-choroid-Bruch’s membrane complex. […] Subsequently, complement attack (membrane attack complex activation) leads to collateral damage of retinal tissue.
#1 Pathophysiology of AMD: Vision Loss Information | Vision RELIEF
https://provider-amd.vision-relief.com/pathophysiology-of-amd/
Age-related macular degeneration (AMD) is a progressively deteriorating eye condition primarily impacting the macula, the central portion of the retina responsible for high-acuity vision. AMD is characterized by the increasing presence and size of drusen, pigmentary changes in the RPE, atrophy of retinal cells, and potentially growth of abnormal blood vessels under the retina, known as choroidal neovascularization. […] While not fully understood, a number of factors are implicated in the pathogenesis of AMD: […] The retina is vulnerable to oxidative damage because of its high oxygen consumption and exposure to light, which leads to the accumulation of such damage and results in cellular dysfunction and death. […] Chronic low-grade inflammation plays a crucial role in AMD progression. This inflammation damages the RPE, photoreceptor cells, and choroidal vessels and may lead to geographic atrophy. The complement system, a part of the innate immune response, is particularly implicated.
#1 Role of Mitochondrial Dysfunction in Dry Age-Related Macular Degeneration – Retina Today
https://retinatoday.com/articles/2015-may-june/role-of-mitochondrial-dysfunction-in-dry-age-related-macular-degeneration
Mitochondrial dysfunction induced by environmental toxicants may be an important risk factor in the etiology of dry age-related macular degeneration (AMD). […] The pathogenesis of dry AMD is multifactorial, and it includes aging, genetic abnormalities, systemic health, environmental risk factors (including cigarette smoking), and mitochondrial dysfunction. […] Mitochondrial dysfunction has been implicated in the etiology of dry AMD. […] Mitochondrial dysmorphology observed in RPE in eyes with AMD is consistent with severe dysfunction, and mitochondrial DNA from these eyes demonstrate increased oxidative damage. […] A novel mitochondrial protective compound, MTP-131 (Ocuvia, Stealth BioTherapeutics), is a topical ophthalmologic investigational drug under development to treat both common and rare eye disorders, including retinal diseases and inherited mitochondrial optic neuropathies.
#1 A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration | Nature Communications
https://www.nature.com/articles/s41467-019-11262-1
The AREDS trials showed that, among patients with intermediate AMD, antioxidants lower the risk of developing advanced AMD. […] Genetic studies have identified complement pathway gene variants with AMD risk, which strongly implicates the complement pathway in driving AMD progression. […] However, the assumption that these variants induce excessive complement activation that leads to tissue injury remains unvalidated. […] In dry AMD, RPE mitochondrial mass is reduced, mitochondria are morphologically abnormal, and mitochondrial DNA (mtDNA) damage increases with disease severity. […] Photoreceptor cell death is the basis for permanent visual decline in dry AMD. […] Therefore, identifying the mechanisms involved in photoreceptor death is critical for developing new treatments to prevent permanent visual loss.
#1 Role of Mitochondrial Dysfunction in Dry Age-Related Macular Degeneration – Retina Today
https://retinatoday.com/articles/2015-may-june/role-of-mitochondrial-dysfunction-in-dry-age-related-macular-degeneration
Our research has shown that RPE mitochondria are a major target of HQ in the eye, and that HQ exposure induces acute and chronic mitochondrial dysfunction resulting in biochemical and cellular changes consistent with dry AMD. […] In cell culture, MTP-131 prevented HQ-induced mitochondrial dysfunction, activation of biochemical injury pathways, and cellular functions associated with deposits. […] MTP-131 prevented HQ-induced mitochondrial dysfunction, biochemical injury pathways, and deposit formation in a mouse model.
#1 Dry age-related macular degeneration and age-related macular degeneration pathogenesis | Ento Key
https://entokey.com/dry-age-related-macular-degeneration-and-age-related-macular-degeneration-pathogenesis/
Clinical manifestations of dry age-related macular degeneration (AMD) include drusen, retinal pigment epithelium (RPE) hyperplasia, RPE depigmentation, and geographic atrophy (GA). […] GA is an important cause of moderate and severe visual loss among AMD patients. […] The abnormal extracellular matrix (ECM) of AMD eyes includes basal laminar deposit, basal linear deposit, and their clinically evident manifestation, soft drusen. […] Areas of GA have a loss of RPE cells as well as overlying photoreceptors and subjacent choriocapillaris atrophy. […] Lipofuscin comprises a group of autofluorescent lipidprotein aggregates present in nonneuronal and neuronal tissues. […] The reaction product of ethanolamine and two retinaldehyde molecules, A2E, is the major photosensitizing chromophore in lipofuscin that causes reactive oxygen species (ROS) production.
#1 The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products
https://www.mdpi.com/2227-9717/10/4/678
Age-related macular degeneration (AMD) is initiated by retinal pigment epithelium (RPE) cell death, finally leading to neovascularization in the macula lutea. […] RPE cell death is related to oxidative stress, inflammation, and carbonyl stress. […] The important pathogenic factors of AMD are bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), especially A2E-epoxides and blue light. […] A2E is a very unstable pigment, which easily changes to its oxidized form (A2E-epoxide) and, during A2E oxidization, many reactive oxygen species (ROSs) are produced. […] A2E can be changed to A2E-epoxide by blue light, and, at the same time, many ROS, such as H2O2, O2â, and OHÂ·, can be synthesized and start the oxidization of RPEs, thus destroying them. […] Although drusen is one of the hallmarks for discriminating AMD, there are many debates regarding drusen formation. However, it is related to both RPE cell death and ROS synthesis via A2E oxidization.
#1 Dry AMD: From Theory to Treatment
https://www.reviewofophthalmology.com/article/dry-amd-from-theory-to-treatment
Late stage age-related macular degeneration is classified as dry or wet according to characteristic features of these two pathogenic modes. The dry form, which in its end stage is termed geographic atrophy, is characterized by localized regions of atrophy of the retinal pigment epithelium with associated overlying regions of photoreceptor cell death. […] Molecular properties of the choroid/ Bruch’s membrane/RPE axis and subsequent perturbations occurring during aging have been extensively studied in order to identify the mechanistic pathways responsible for AMD pathogenesis. Alterations in pigmentation, accumulation of toxic lipofuscin pigments, and formation of drusen, which are extracellular deposits that accumulate between the RPE and Bruch’s membrane, are all hallmark features of AMD. […] The production of one such lipofuscin fluorophore, A2E, is a marker for RPE dysfunction and is significantly associated with AMD pathogenesis. […] Recent genetic evidence correlating complement factors with AMD risk strongly supports a major inflammatory component for AMD pathogenesis.
#1 Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration | Cell Death & Disease
https://www.nature.com/articles/cddis2016453
Age-related macular degeneration (AMD) is a devastating neurodegenerative disease and a major cause of blindness in the developed world. […] the molecular mechanisms of AMD pathogenesis remain poorly understood. […] Our study provides insights into AMD cellular and molecular mechanisms, proposes dysfunctional autophagy as an underlying mechanism contributing to the pathophysiology of the disease, and opens up new avenues for development of novel treatment strategies. […] AMD is a multifactorial disease and its pathogenesis remains largely elusive. […] Impaired RPE function in dry AMD causes the formation of extracellular deposits called drusen, which accumulate between the RPE and Bruchs membrane (BM). […] Autophagy is a lysosome-mediated degradation process for non-essential or damaged cellular constituents to supply the cell with energy and to maintain homeostasis.
#1 Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration | Cell Death & Disease
https://www.nature.com/articles/cddis2016453
Recently, dysregulated autophagy in RPE was shown to increase susceptibility to oxidative stress and AMD. […] Here, we analyzed the phenotype and function of RPE cultures established from human donor eyes. […] our study suggests that impaired autophagy dynamics in RPE contributes to the pathophysiology of AMD. […] Dysfunctional autophagy in RPE could lead to mitochondrial disintegration by affecting the mitochondrial fission/fusion ratio that is crucial for maintaining functional mitochondria. […] Dysfunctional mitochondria in AMD RPE can further translate into an increased oxidative stress response and a shift from oxidative phosphorylation to glycolytic ATP production. […] Our studies identify specific disease phenotypes in a novel model for human AMD, and suggest that dysfunctional autophagy in RPE contributes to the pathophysiology of AMD.
#1 Mechanisms of age-related macular degeneration
https://pmc.ncbi.nlm.nih.gov/articles/PMC3404137/
An important route of communication and recurring theme in AMD pathology is the crosstalk of RPE with immune and vascular systems. […] The activity of the enzyme DICER1 is sufficiently broad-reaching that it is an attractive candidate as a choreographer of retinal health and homeostasis. […] The cumulative burden on the RPE may, or may not, converge to a single pathway that determines RPE cell viability. […] The Alu RNAs that accumulate in DICER1 deficiency are transcribed from Alu DNA sequences in the nuclear genome. […] The deleterious effect of Alu sequences is often ascribed to a single retrotransposition event; for example, an Alu sequence may insert into a critical gene, thereby disrupting gene function.
#1 Geographic Atrophy – EyeWiki
https://eyewiki.org/Geographic_Atrophy
Geographic atrophy (GA) is a chronic progressive degeneration of the macula as part of late-stage age-related macular degeneration (AMD). The disease is characterized by localized sharply demarcated atrophy of outer retinal tissue, retinal pigment epithelium (RPE), and choriocapillaris. […] The pathogenesis of GA remains unclear. The natural course of AMD begins with early stages that are characterized by the presence of drusen, which are yellow deposits between the retinal pigment epithelium and Bruchs membrane. […] The cause of GA is not fully known, though it has been studied extensively. Genetic and environmental factors seem to contribute substantially. Complement factor H variant Y402H and ARMS2 have been associated with an increased risk of GA development. […] Oxidative stress and low-grade inflammation seem to play a role in AMD. […] New research is indicating that direct RNA toxicity, specifically Alu RNA mediated inflammation, might play a significant role in the pathogenesis of GA.
#1
https://www.jci.org/articles/view/71029
AMD is now one of the best-understood complex, multifactorial diseases. […] Various additional pathways have been implicated, including oxidative stress, impairment of lysosomal degradation with accumulation of retinal toxins, local inflammation, complement system dysfunction, and VEGF hyperexpression. […] The retina provides an ideal environment for the generation of ROS due to its specific anatomical and metabolic characteristics. […] With increasing age and disease, lipofuscin accumulates in the lysosomal compartment of postmitotic RPE cells due to the incomplete degradation of the photoreceptor outer segments. […] In exudative AMD, CNV has been shown to be associated with inflammatory cells. […] The role of the alternative complement pathway in AMD pathogenesis has been underscored by the discovery of an association between CFH and other risk-conferring polymorphisms in this pathway.
#1 Macular degeneration – Wikipedia
https://en.wikipedia.org/wiki/Macular_degeneration
Early work demonstrated a family of immune mediators was plentiful in drusen. […] Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced. […] The three loci where identified gene variants are found are designated: Complement Factor H (CFH) on chromosome 1 at location 1q31.3, HTRA serine peptidase 1/Age Related Maculopathy Susceptibility 2 (HTRA1/ARMS2) on chromosome 10 at location 10q26, Complement Factor B/Complement Component 2 (CFB/CC2) on chromosome 6 at 6p21.3. […] The pathophysiology of geographic atrophy is still uncertain. […] The aging pigment lipofuscin can be broken down with the help of melanin and drugs through a newly discovered mechanism.
#1 The Pipeline for Dry Macular Degeneration
https://www.reviewofophthalmology.com/article/the-pipeline-for-dry-macular-degeneration
Ample evidence has established oxidative stress as an important contributor in the pathogenesis of AMD. The formation of reactive oxygen species not only appears to damage the retinal pigment epithelium but also impairs local complement inhibition, exacerbating local inflammatory processes that contribute to progression of AMD. Additionally, a polymorphism in mitochondrial DNA (A4917G), which is involved in both DNA repair and control of oxidative stress, has been found to increase the risk of AMD. […] Strong evidence now exists that implicates the complement pathway as a key mechanism in the pathogenesis of AMD. Polymorphic variants in genes encoding complement factor H, complement component 3, and age-related maculopathy susceptibility 2 have been shown to significantly increase the risk of developing AMD. Histological analysis of patients with AMD has also revealed the presence of complement component 5 as well as the terminal membrane attack complex, C5b-9, within drusen.
#1 A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration | Nature Communications
https://www.nature.com/articles/s41467-019-11262-1
The mechanisms for RPE cell death may differ from those of photoreceptors. […] Since cell death pathways are redundant and complementary, combination therapies that block both apoptosis and necrosis may be effective for dry AMD. […] Future directions in dry AMD research should emphasize systems biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy.
#1 Age-Related Macular Degeneration – EyeWiki
https://eyewiki.org/Age-Related_Macular_Degeneration
The degenerating retina succumbs to the final end point of geographic atrophy, choroidal neovascularization and pigment epithelial detachment. […] Treatments targeting intermediate disease mechanisms or initiating disease factors are in the minority, but may offer a more successful approach to vision preservation than those targeting relatively later steps in AMD pathophysiology (i.e., choroidal neovascularization). […] Complement factor H (CFH) is an important gene in the pathogenesis of AMD. […] Biochemical pathways and genetic association studies have shed light on the possible biochemical pathways that go awry in AMD. […] The complement system is a three-pronged pathway involved in natural and acquired immunity. […] Activation of the complement system results in cellular damage that is central in the pathogenesis of dry and wet forms of AMD, and this is supported by the presence of many complement system proteins within drusen in patients with AMD.
#1
https://journals.lww.com/apjoo/fulltext/2023/03000/the_role_of_inflammation_in_age_related_macular.4.aspx
Complement system dysfunction in dry AMD and GA has been further supported by the evidence of genetic variants characterizing AMD patients, associated with its abnormal upregulation. […] The high importance of complement system activation in the pathogenesis of AMD and GA stimulated companies in developing therapies targeting complement factors. […] The imaging counterpart of proinflammatory activity in AMD is represented by the optical coherence tomography (OCT)-detected hyperreflective foci (HF). […] The presence of these hyperreflective discrete dots, detected on structural optical coherence tomography, characterizes both the outer retina and the choroid, and are better highlighted by inverted white-black color optical coherence tomography. […] Overall considering all the aspects discussed in the present survey, AMD pathogenetic mechanisms are more complex than a mere proangiogenic activity.
#1 Age-Related Macular Degeneration (AMD or ARMD) – Eye Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/eye-disorders/retinal-disorders/age-related-macular-degeneration-amd-or-armd
Dry (nonexudative or atrophic): All age-related macular degeneration (AMD) starts as the dry form. About 85% of people with AMD have only dry AMD. […] Dry AMD causes changes of the retinal pigment epithelium, typically visible as dark pinpoint areas. The retinal pigment epithelium plays a critical role in keeping the cones and rods healthy and functioning well. Accumulation of waste products from the rods and cones can result in drusen, which appear as yellow spots. Areas of chorioretinal atrophy (referred to as geographic atrophy) occur in more advanced cases of dry AMD. There is no elevated macular scar (disciform scar), edema, hemorrhage, or exudation. […] In 2023, intravitreal pegcetacoplan and intravitreal avacincaptad pegol became available for the treatment of advanced dry AMD due to geographic atrophy. These medications inhibit the complement pathway and can slow the progression of geographic atrophy.
#1
https://link.springer.com/article/10.1007/s00018-016-2147-8
The ultimate mechanism remains to be clarified but in primary human lung epithelial cells, MAC triggered NLRP3 inflammasomes by increasing the intracellular Ca2+ concentration with the subsequent loss of the mitochondrial transmembrane potential. […] There are many other danger signals for NLRP3 inflammasomes in the RPE, e.g. accumulation of Alu RNA, the appearance of the lipid peroxidation end product HNE (4-hydroxynonenal), as well as the presence of intracellular protein aggregates accompanied by a decline in the efficiency of autophagy. […] Although RPE and retinal inflammatory cells can produce both inflammasome-dependent cytokines, the cytokine release can be biased towards either IL-1 or IL-18. […] The multitude of inflammation-related plasma proteins in the drusen refers to the involvement of systemic immunological processes in the pathogenesis of AMD.
#1 The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products
https://www.mdpi.com/2227-9717/10/4/678
Accumulated drusen not only induces central region blindness, but also stimulates inflammation in RPE, and the exacerbation of an inflammatory response is a trigger of AMD occurrence. […] The oxidative stress is closely connected with inflammation, and, in particular, A2E stimulates RPE cell inflammation by increasing the level of IL-1Î² via the NLRP3 inflammasome. […] From the toxicological point of view, although each type of stress can induce RPE cells to be damaged by itself, all of them participate via their toxicological network in AMD occurrence via RPE cell apoptosis.
#1 Pathogenic Mechanisms
https://amdbook.org/book/export/html/21
With all of the above in mind, Zarbin has summarized his review on AMD pathogenesis in five sequential steps as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes RPE and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix, which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and (5) the abnormal extracellular matrix results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, patient’s susceptibility to AMD would be determined by both the environment and his genetic profile.
#1 Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions | British Journal of Ophthalmology
https://bjo.bmj.com/content/106/3/297
AMD is a complex disease with several pathways plausibly involved in its pathogenesis, which poses therapeutic challenges. For the time being, the management of dry AMD depends greatly on observation, lifestyle changes, frequent follow-up evaluations, early recognition of visual deterioration and CNV detection. Several therapeutic avenues to reduce the rate of disease progression are being investigated, including (1) drugs with antioxidative properties, (2) inhibitors of the complement cascade, (3) neuroprotective agents, (4) visual cycle inhibitors, (5) gene therapy and (6) cell-based therapies, among others.
#2 Mechanisms of age-related macular degeneration
https://pmc.ncbi.nlm.nih.gov/articles/PMC3404137/
Age-related macular degeneration (AMD), a progressive condition that is untreatable in up to 90% of patients, is a leading cause of blindness in the elderly worldwide. […] In contrast, there are not any approved treatments for dry AMD. […] Emerging models of dry AMD pathogenesis are presented, with a focus on DICER1 deficit and the toxic accumulation of retinal debris. […] The critical event in AMD pathogenesis, from which there is no return, is RPE dysfunction and degeneration. […] The molecular hallmarks of dry AMD are toxic accumulations, either within the RPE cell or at the RPE-BrM interface. […] We propose adding AMD to this list. The mitochondrial defects observed in the RPE of AMD eyes include DNA mutations, impaired structural integrity, and defective mitochondrial function.
#2 Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions | British Journal of Ophthalmology
https://bjo.bmj.com/content/106/3/297
Age-related macular degeneration (AMD) is a complex multifactorial disease whose pathogenesis is incompletely understood and evolving, with a detailed evaluation behind the scope of this review. Several factors are believed to contribute to its pathogenesis, including genetic, oxidative stress, environmental, inflammatory and ischaemic. The presence of drusen is considered the hallmark of earlier stages of AMD, which may enlarge, become confluent and evolve to drusenoid retinal pigmented epithelium (RPE) detachments. This causes a disruption in the interaction between Bruchs membrane and RPE, inhibiting RPE function, including the crucial ability to transport photoreceptor debris across Bruchs membrane to the choriocapillaris, further facilitating accumulation of lipofuscin and other related products including A2E.
#2 Dry age-related macular degeneration and age-related macular degeneration pathogenesis | Ento Key
https://entokey.com/dry-age-related-macular-degeneration-and-age-related-macular-degeneration-pathogenesis/
Clinical manifestations of dry age-related macular degeneration (AMD) include drusen, retinal pigment epithelium (RPE) hyperplasia, RPE depigmentation, and geographic atrophy (GA). […] GA is an important cause of moderate and severe visual loss among AMD patients. […] The abnormal extracellular matrix (ECM) of AMD eyes includes basal laminar deposit, basal linear deposit, and their clinically evident manifestation, soft drusen. […] Areas of GA have a loss of RPE cells as well as overlying photoreceptors and subjacent choriocapillaris atrophy. […] Lipofuscin comprises a group of autofluorescent lipidprotein aggregates present in nonneuronal and neuronal tissues. […] The reaction product of ethanolamine and two retinaldehyde molecules, A2E, is the major photosensitizing chromophore in lipofuscin that causes reactive oxygen species (ROS) production.
#2 The Role of Inflammation in Age-Related Macular Degeneration
https://www.ijbs.com/v16p2989.htm
Age-related macular degeneration (AMD) is a blinding eye disease which incidence gradually increases with age. Inflammation participates in AMD pathogenesis, including choroidal neovascularization and geographic atrophy. […] In this review, we summarize and discuss the role and mechanism(s) of inflammation, as well as inflammatory cytokines and leukocytes in the pathogenesis of AMD. […] AMD is the consequence of a multifactorial interaction of metabolism, functions, genetics and the environment, and these multiple factors foster a stage conducive for the chronic structural changes in the macular area (choriocapillaries, Bruch’s membrane (BM), RPE, photoreceptor). […] Thus, inflammation is believed to play indispensable roles in the pathogenesis of both dry and wet AMD. […] In dry AMD, with the accumulation of lipofuscin and destruction of phagocytic activity of lysosomal enzymes, photoreceptors and RPE cells are damaged. Inflammatory cells release cytokines to attract more inflammatory cells. […] Therefore, it is speculated that inflammation plays different roles in the pathogenesis of wet and dry AMD, respectively.
#2 Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions | British Journal of Ophthalmology
https://bjo.bmj.com/content/106/3/297
Several studies suggest that complement pathway activation and the consequent membrane attack complex (MAC) play a key role in choriocapillaris loss and in the development of AMD and GA. Mullins et al correlated vascular loss and choriocapillaris density with the extent of drusen, suggesting that in early stages, the deposition of complement complexes induces loss of choriocapillaris and drusen formation. Subsequently, the same group observed the deposition of MAC in the outer part of Bruchs membrane prior to choriocapillaris loss and identified that the high-risk allele Y402H in CFH (OMIM #134370) is associated with elevated levels of MAC and increased risk of choriocapillaris loss in early AMD disease. Polymorphisms in multiple other genes have also been associated with increased risk of developing AMD, including genes involved in the complement cascade, ARMS2 (OMIM #611313), ABCA4 (OMIM #601691), and HTRA1 (OMIM #602194). It is still unclear if these genetic risk alleles are associated with the development of either wet or dry AMD, or both.
#2 Age-Related Macular Degeneration – EyeWiki
https://eyewiki.org/Age-Related_Macular_Degeneration
The degenerating retina succumbs to the final end point of geographic atrophy, choroidal neovascularization and pigment epithelial detachment. […] Treatments targeting intermediate disease mechanisms or initiating disease factors are in the minority, but may offer a more successful approach to vision preservation than those targeting relatively later steps in AMD pathophysiology (i.e., choroidal neovascularization). […] Complement factor H (CFH) is an important gene in the pathogenesis of AMD. […] Biochemical pathways and genetic association studies have shed light on the possible biochemical pathways that go awry in AMD. […] The complement system is a three-pronged pathway involved in natural and acquired immunity. […] Activation of the complement system results in cellular damage that is central in the pathogenesis of dry and wet forms of AMD, and this is supported by the presence of many complement system proteins within drusen in patients with AMD.
#2 Pathogenic Mechanisms
https://amdbook.org/book/export/html/21
Age-related changes that predispose to age-related macular degeneration (AMD) occur in the outer retina, more specifically the region that includes the photoreceptors, the RPE, Bruchs membrane and the choriocapillaris. […] The deposition of insoluble material, the calcification and increase in thickness of Bruchs membrane, and a less fenestrated and thinner choriocapillaris leads to photoreceptors/RPE hypoxia. The number of RPE cells reduces with age and in each cell there is a progressive accumulation of lipofuscin during life. Basal laminar and basal linear deposits, drusen, RPE degeneration and atrophy develop and finally, geographic atrophy of RPE and choroidal neovascularization occur. […] Aging is known to be associated with increased oxidative damage and the retina is a fertile environment for reactive oxygen species. Apart from the presence of two retinal blood supplies that generate an highly oxygenated environment, the exposure to high levels of cumulative irradiation, high levels of photosensitizers, large amounts of polyunsaturated fatty acids, readily oxidizable lipid, protein and carbohydrate substrates, and the huge proteolytic burden in the RPE contribute to this particular predisposition to oxidative stress.
#2 Mitochondrial Repair in Dry Age-Related Macular Degeneration | Retinal Physician
https://www.retinalphysician.com/issues/2019/april/mitochondrial-repair-in-dry-age-related-macular-degeneration/
Age-related macular degeneration (AMD) is considered the leading cause of blindness among elderly people in developed countries. […] there is strong evidence that disruption in major mitochondrial metabolic pathways contributes to AMD pathogenesis. […] Molecular genetic studies have shown that AMD patients can have mtDNA SNP variants in their retinas, some of which cause amino acid changes in the proteins. […] Aging is accompanied by deterioration in mitochondrial structure and a decline in their numbers. […] Interestingly, these abnormalities are in the mtDNA but not the nuclear DNA of RPE cells and correlate with the severity of AMD. […] It has been speculated that damaged mitochondria in AMD can lead to increased superoxide production, which further impairs the proteins, lipids, and DNA, creating a vicious cycle of injury.
#2 Mechanism of Action of Elamipretide in Dry AMD Patients with GA
https://www.hcplive.com/view/mechanism-of-action-of-elamipretide-for-ga-in-dry-amd
Khanani: When looking at the mechanism of action to help patients with dry AMD, the approved treatments target the complement system, but another exciting potential pathway is to work on mitochondria. We know that progressive mitochondrial dysfunction contributes to AMD. Retinal pigment epithelium (RPE) mitochondria in AMD eyes undergo more pronounced degenerative changes and changes in retinal bioenergetics play a key role in vision loss. Mitochondrial dysfunction in photoreceptors can lead to ellipsoid zone (EZ) attenuation and vision loss. EZ is a mitochondrial-rich portion of photoreceptors visible on optical coherence tomography (OCT) and the mitochondria within the EZ support the high metabolic demands of photoreceptors. […] In terms of these targets, I think retinal mitochondrial dysfunction is a druggable target, and that’s why, if we can have a drug that can target mitochondria and avoid this dysfunction, we may be able to control the disease and have the sick mitochondria now functioning at a better level, leading to a slowing down of disease, or improvement in disease or improvement in vision outcomes.
#2
https://link.springer.com/article/10.1007/s00018-016-2147-8
AMD is a progressive eye disease that has been linked with several pathological factors, i.e. chronic oxidative stress, autophagy decline, and inflammation. […] A reduction of intracellular inflammation in conjunction with the prevention of RPE and photoreceptor loss all have central roles in programmes developing novel therapy options for AMD. […] The RPE, a single-cell layer at the posterior part of the eye plays a significant role in the pathogenesis of AMD. […] Continuous ingestion of POS material by non-dividing and aging RPE cells results in the accumulation of an undegradable and autofluorescent metabolite called lipofuscin in lysosomes, which inhibits autophagy by blocking the function of lysosomal enzymes, i.e. it combines oxidative stress with retinal inflammation. […] Inflammasome activation in the RPE was reported for the first time in 2012.
#2 Dry AMD: From Theory to Treatment
https://www.reviewofophthalmology.com/article/dry-amd-from-theory-to-treatment
Late stage age-related macular degeneration is classified as dry or wet according to characteristic features of these two pathogenic modes. The dry form, which in its end stage is termed geographic atrophy, is characterized by localized regions of atrophy of the retinal pigment epithelium with associated overlying regions of photoreceptor cell death. […] Molecular properties of the choroid/ Bruch’s membrane/RPE axis and subsequent perturbations occurring during aging have been extensively studied in order to identify the mechanistic pathways responsible for AMD pathogenesis. Alterations in pigmentation, accumulation of toxic lipofuscin pigments, and formation of drusen, which are extracellular deposits that accumulate between the RPE and Bruch’s membrane, are all hallmark features of AMD. […] The production of one such lipofuscin fluorophore, A2E, is a marker for RPE dysfunction and is significantly associated with AMD pathogenesis. […] Recent genetic evidence correlating complement factors with AMD risk strongly supports a major inflammatory component for AMD pathogenesis.
#2 The Age-Related Macular Degeneration (AMD)-Preventing Mechanism of Natural Products
https://www.mdpi.com/2227-9717/10/4/678
Accumulated drusen not only induces central region blindness, but also stimulates inflammation in RPE, and the exacerbation of an inflammatory response is a trigger of AMD occurrence. […] The oxidative stress is closely connected with inflammation, and, in particular, A2E stimulates RPE cell inflammation by increasing the level of IL-1Î² via the NLRP3 inflammasome. […] From the toxicological point of view, although each type of stress can induce RPE cells to be damaged by itself, all of them participate via their toxicological network in AMD occurrence via RPE cell apoptosis.
#2 Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration | Cell Death & Disease
https://www.nature.com/articles/cddis2016453
Recently, dysregulated autophagy in RPE was shown to increase susceptibility to oxidative stress and AMD. […] Here, we analyzed the phenotype and function of RPE cultures established from human donor eyes. […] our study suggests that impaired autophagy dynamics in RPE contributes to the pathophysiology of AMD. […] Dysfunctional autophagy in RPE could lead to mitochondrial disintegration by affecting the mitochondrial fission/fusion ratio that is crucial for maintaining functional mitochondria. […] Dysfunctional mitochondria in AMD RPE can further translate into an increased oxidative stress response and a shift from oxidative phosphorylation to glycolytic ATP production. […] Our studies identify specific disease phenotypes in a novel model for human AMD, and suggest that dysfunctional autophagy in RPE contributes to the pathophysiology of AMD.
#2 Macular degeneration – Wikipedia
https://en.wikipedia.org/wiki/Macular_degeneration
Early work demonstrated a family of immune mediators was plentiful in drusen. […] Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced. […] The three loci where identified gene variants are found are designated: Complement Factor H (CFH) on chromosome 1 at location 1q31.3, HTRA serine peptidase 1/Age Related Maculopathy Susceptibility 2 (HTRA1/ARMS2) on chromosome 10 at location 10q26, Complement Factor B/Complement Component 2 (CFB/CC2) on chromosome 6 at 6p21.3. […] The pathophysiology of geographic atrophy is still uncertain. […] The aging pigment lipofuscin can be broken down with the help of melanin and drugs through a newly discovered mechanism.
#2
https://www.jci.org/articles/view/178296
Careful regulation of the complement system is critical for enabling complement proteins to titrate immune defense while also preventing collateral tissue damage from poorly controlled inflammation. […] Dysregulated complement activation contributes to parainflammation, a low level of inflammation triggered by cellular damage that functions to reestablish homeostasis, or outright inflammation that disrupts the visual axis. Complement dysregulation has been implicated in many ocular diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). […] In the last two decades, complement activity has been the focus of intense investigation in AMD pathogenesis, leading to the development of novel therapeutics for the treatment of atrophic AMD. […] In this Review, we focus on the contribution of complement to the pathophysiology of age-related macular degeneration (AMD), highlighting the clinical development of complement-targeting therapeutics for dry AMD.
#2 A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration | Nature Communications
https://www.nature.com/articles/s41467-019-11262-1
The mechanisms for RPE cell death may differ from those of photoreceptors. […] Since cell death pathways are redundant and complementary, combination therapies that block both apoptosis and necrosis may be effective for dry AMD. […] Future directions in dry AMD research should emphasize systems biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy.
#2
https://journals.lww.com/apjoo/fulltext/2023/03000/the_role_of_inflammation_in_age_related_macular.4.aspx
Although inflammation has been more investigated in the wet form of AMD, it undoubtedly takes a major role also in dry AMD. […] The chronicity of these phenomena is responsible for the onset and progression of a proinflammatory microenvironment, acting as a further source of RPE and photoreceptors cells damage. […] The occurrence of a wide proinflammatory activity is supported by the evidence of increased levels of several cytokines and proinflammatory mediators found both in humans and in animal models of AMD. […] The increased level of these cytokines allowed to advance the hypothesis also of T-cell lymphocytes-mediated phenomena in the pathogenesis of AMD. […] If ILs and cytokines are important proinflammatory factors in dry AMD, culminating in the activation of the inflammasome complex, even growing evidence highlighted a major role of the complement system activation.
#2 Dry Age Macular Degeneration (Dry AMD) Market to Reach a CAGR of 4.64% during 2024-2034, Impelled by Anti-Angiogenic Drugs – BioSpace
https://www.biospace.com/dry-age-macular-degeneration-dry-amd-market-to-reach-a-cagr-of-4-64-during-2024-2034-impelled-by-anti-angiogenic-drugs
The dry age macular degeneration (Dry AMD) market is witnessing a surge in the development of novel therapeutic agents, that aim to address the underlying mechanisms of the disease and slow its progression. […] However, recent advancements have introduced new pharmacological approaches that target specific pathways implicated in Dry AMD pathogenesis. One notable example is the development of complement pathway inhibitors. […] Research has identified inflammation and oxidative stress as key contributors to the pathophysiology of Dry AMD. […] Consequently, drugs targeting these pathways are being investigated. […] Gene therapy approaches, such as those targeting the complement factor H gene, aim to provide long-term benefits by correcting genetic defects associated with the disease. […] Another significant advancement in gene therapy for Dry AMD is the use of adeno-associated virus (AAV) vectors to deliver therapeutic genes to retinal cells.
#2 Geographic Atrophy – Advanced Form of Dry Macular Degeneration
https://www.macular.org/about-macular-degeneration/geographic-atrophy
If dry AMD advances to geographic atrophy, early intervention offers your best chance to preserve useful sight. […] Syfovre (pegcetacoplan) is administered monthly, or every other month, by injection into the eye, and works by targeting a protein in the complement system known as C3. […] Izervay (avacincaptad pegol) is another treatment option for GA, and is given as an eye injection once a month, for up to 12 months. […] Izervay works by blocking excess production of the C5 protein, part of the immune systems early response system, which researchers believe causes the development of GA lesions and scarring that cause vision loss.
#2 Pathogenic Mechanisms
https://amdbook.org/book/export/html/21
With all of the above in mind, Zarbin has summarized his review on AMD pathogenesis in five sequential steps as follows: (1) AMD involves aging changes plus additional pathological changes (ie, AMD is not just an aging change); (2) in aging and AMD, oxidative stress causes RPE and, possibly, choriocapillaris injury; (3) in AMD (and perhaps in aging), RPE and, possibly, choriocapillaris injury results in a chronic inflammatory response within the Bruch membrane and the choroid; (4) in AMD, RPE and, possibly, choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix, which causes altered diffusion of nutrients to the retina and RPE, possibly precipitating further RPE and retinal damage; and (5) the abnormal extracellular matrix results in altered RPE-choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or choroidal new vessel growth. In this sequence of events, patient’s susceptibility to AMD would be determined by both the environment and his genetic profile.
#2 Macular Degeneration Treatment | BrightFocus Foundation
https://www.brightfocus.org/macular/treatments/
People with intermediate-stage dry AMD may benefit from taking a special mix of supplements to decrease their risk of losing central vision. […] In clinical trials, an over-the-counter combination of vitamins and minerals called the AREDS2 formula showed benefit in preventing the progression of intermediate dry AMD to late dry AMD. […] Two U.S. Food and Drug Administration-approved treatments for dry AMD are intended for people in a late stage of the disease who have been diagnosed with geographic atrophy. […] The first, Syfovre, was approved in February 2023, followed by Izervay in September 2023. […] Both are injections shown to reduce the rate of geographic atrophy lesion growth. […] In 2024, the Valeda Light Delivery System was approved for use in dry AMD. […] Valeda uses multiple wavelengths of light (red and near-infrared) to stimulate cellular processes within the retina, including mitochondrial activity, which can help reduce inflammation and promote healthy cell function.
#3 The Pathogenesis of Dry Age-related Macular Degeneration – Retina Today
https://retinatoday.com/articles/2011-apr/the-pathogenesis-of-dry-age-related-macular-degeneration
Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. AMD is commonly divided into two main subtypes: dry AMD, a form of slowly progressive geographic atrophy of the macula, and wet AMD, which rapidly progresses to blindness and involves abnormal formation of blood vessels in the macula, a process known as choroidal neovascularization (CNV). […] The complexity of pathologic changes associated with dry AMD makes it more difficult to study. A number of both genetic and induced animal models representative of dry AMD have been developed with the prospect of mapping the pathologic mechanisms that trigger the onset of disease. Uncovering these mechanisms would enable the development of both innovative diagnostic assays to detect initial stages of the disease and targeted therapies focused on prevention and early treatment.
#3 Age-Related Macular Degeneration – EyeWiki
https://eyewiki.org/Age-Related_Macular_Degeneration
In AMD, it is believed that an early „seeding event,” such as an area of retinal pigment epithelium atrophy with cellular debris, induces innate immune system activation at the RPE-choroid-Bruch’s membrane complex. […] Subsequently, complement attack (membrane attack complex activation) leads to collateral damage of retinal tissue.
#3 Dysfunctional autophagy in RPE, a contributing factor in age-related macular degeneration | Cell Death & Disease
https://www.nature.com/articles/cddis2016453
Recently, dysregulated autophagy in RPE was shown to increase susceptibility to oxidative stress and AMD. […] Here, we analyzed the phenotype and function of RPE cultures established from human donor eyes. […] our study suggests that impaired autophagy dynamics in RPE contributes to the pathophysiology of AMD. […] Dysfunctional autophagy in RPE could lead to mitochondrial disintegration by affecting the mitochondrial fission/fusion ratio that is crucial for maintaining functional mitochondria. […] Dysfunctional mitochondria in AMD RPE can further translate into an increased oxidative stress response and a shift from oxidative phosphorylation to glycolytic ATP production. […] Our studies identify specific disease phenotypes in a novel model for human AMD, and suggest that dysfunctional autophagy in RPE contributes to the pathophysiology of AMD.
#3
https://www.jci.org/articles/view/178296
Complement dysregulation contributes to multiple ocular diseases and is a major contributor to AMD pathogenesis specifically. Investigation into complement activity in the posterior segment of the eye in the context of AMD has led to recent major advancements in therapies for atrophic AMD, a disease that was previously untreatable.