Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential
Abstract
:1. Introduction
Pathogenesis
2. Methods
3. Results
3.1. AMD Genomics
3.1.1. Immune Response and Complement Genes
Complement Factor H (CFH)
Complement-Factor-H-Related (CFHR)
Complement C3
Complement Factor B/Complement 2 (CFB/C2)
Complement C9
Complement Factor I (CFI)
Other Genetic Variants
3.1.2. PLEKHA/ARMS2/HTRA-1
3.1.3. Oxidative Stress Genes
Manganese Superoxide Dismutase (MnSOD)
Iron Homeostasis Genes
3.1.4. Lipid Metabolism Genes
Apolipoproteins (Apo)
ATP-Binding Cassette Family: ABCA1 and ABCA4
Hepatic Lipase (LIPC)
3.1.5. Cell Survival Genes
DNA Damage Repairing
Nuclear Factor Kappa B (NF-κb)
3.1.6. Neovascularisation
Vascular Endothelial Growth Factor (VEGF)
Tissue Inhibitor of Matrix Metalloproteinase 3 (TIMP3)
3.1.7. Extracellular Matrix Alterations
3.2. Clinical Applications
3.2.1. Association with Particular Clinical Subtypes of AMD
3.2.2. Detection of Bio-Markers
3.2.3. Genetic Tests
Prediction of Risk Profile
Response to Therapy
3.3. Future Perspectives
3.3.1. Development of Personalized Treatments
Complement
3.3.2. Gene Therapy in AMD
Anti-VEGF
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Environmental Factors | No Modifiable | Modifiable |
---|---|---|
AGE | SMOKING | |
EPIGENETICS DNA methylation Chromatine changes Histone acetylation miRNA | NUTRITION | |
ALCOHOL | ||
LIGHT EXPOSURE | ||
HIGH BLOOD PRESSURE |
Pathway | Molecule | Polymorphism | Evidence |
---|---|---|---|
Immune response and complement genes | CFH | rs1061170, rs10922109, rs121913059 | Fritsche et al., 2016 [33], Edwards et al., 2005 [35], Park et al., 2019 [36], Herrsterbeek et al., 2020 [37], Ferreira et al., 2009 [38] |
C3 | rs2230199, rs1047286 | Maller et al., 2007 [39], Thakkinstian et al., 2010 [40] | |
CFB | rs641153, rs415667 | Wang et al., 2013 [41], Thakkinstian et al., 2012 [42] | |
C2 | rs9332739, rs547154 | Wang et al., 2013 [41], Thakkinstian et al., 2012 [42] | |
C9 | rs62358361, rs34882957 | Fritsche et al., 2016 [33], Seddon et al., 2013 [43], | |
CFI | rs2285714, rs10033900 | Ven et al., 2013 [44], Wang et al., 2016 [45] | |
other | PLEKHA/ARMS2/HTRA-1 | rs10490924, rs11200638 | Kanda et al., 2007 [46], Mullins et al., 2019 [47], Zhang et al., 2021 [48], Liu et al., 2020 [49], DeWan et al., 2006 [50], Chen et al., 2009 [51] |
Oxidative stress genes | MnSOD | Ala-9Val, Ile58Thr | Kimura et al., 2020 [52], Kowalski et al., 2010 [53] |
HMOX1 HMOX2 | rs2071747, rs2270363 | Synowiec et al., 2012 [54] | |
Lipid metabolism genes | ApoE | rs429358 | Fritsche et al., 2016 [33] |
ABCA1 | rs2740488 | Fritsche et al., 2016 [33] | |
LIPC | rs0468017, rs493258, rs2043085 | Yu et al., 2011 [55], Fritsche et al., 2016 [33] | |
Neovascularisation genes | VEGF | rs943080 | Zaho et al., 2013 [56], Balikova et al., 2019 [57] |
Complement | ||||||
---|---|---|---|---|---|---|
Antagonist | Therapeutic (Alt. Name) | Pharma Company | Treatment Type | Complement Target | Administration | Clinical Trials |
GEM 103 | Gemini Therapeutics | full-length recombinant | CFH | Intravitreal injection | NCT04643886 phase II | |
AMY 101 | Amyndas Pharmaceuticals | peptidic complement inhibitor (mini-FH) | CFH | administrated in healthy male volunteers | ||
IONIS-FB-LRX, | Ionis Pharma | antisense oligonucleotide encoding CFB | CFB | Subcutaneous | NCT03815825 phase II | |
Pegcetacoplan (APL-2) | Apellis Pharmaceuticals | cyclic PEG peptide | C3 | Intravitreal injection | NCT03525613 NCT03525600 phase III | |
LGF 316 + CLG561 | Novartis | IgG1 antibody + anti-properdin antibody | C5 + properdine | Intravitreal injection | NCT02515942 (completed) | |
ZIMURA (ARC1905) | IVERIC bio | pegylated RNA aptamer | C5 | Intravitreal injection | NCT04435366 phase III | |
Gene-Therapy | AAVCAGsCD59 (HMR59) | Janssen Research & Development | AAV gene therapy | CD59 | Single intravitreal injection | NCT03585556 NCT03144999 (completed) |
GT005 | Gyroscope Therapeutics Limited | AAV gene therapy | CFI | Single subretinal injection | NCT03846193 phase I NCT04566445 NCT04437368 phase II |
Anti-Angiogenesis | |||||
---|---|---|---|---|---|
Gene Therapy | Therapeutic (Alt. Name) | Pharms Company | Gene Expression | Administration | Clinical Trials |
AAV2-sFLT01 | Genzyme, a Sanofi Company (Modena, Italy) | sFLT01 | Single intravitreal injection | NCT01024998 phase I | |
RGX-314 | Regenxbio, Inc. Rockville, MD, USA | monoclonal antibody fragment similar to ranizumab | Subretinal via transvitreal injection | NCT04514653, NCT04832724, NCT03999801, NCT05210803, NCT04704921 | |
ADVM-022 | Adverum Biotechnologies (Redwood City, CA, USA) | coding sequence for aflibercept | Single intravitreal injection | NCT03748784 phase I | |
4D-150 | 4D Molecular Therapeutics (Emeryville, CA, USA) | miRNA targeting VEGF-C and sequences encoding aflibercept | Single intravitreal injection | NCT05197270 phase I | |
RetinoStat (OXB-201) | Oxford BioMedica (Oxford, UK) | endostatin and angiostatin | Intravitreal injection | NCT01678872 phase I | |
IBI302 | Innovent Biologics Co. Ltd. (Suzhou, China) | decoy receptor fusion protein | Intravitreal injection | NCT04820452 phase II | |
BD311 | Shanghai BDgene Co., Ltd. (Shanghai, China) | expressing VEGFA antibody | Intravitreal injection | NCT05099094 phase I |
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Stradiotto, E.; Allegrini, D.; Fossati, G.; Raimondi, R.; Sorrentino, T.; Tripepi, D.; Barone, G.; Inforzato, A.; Romano, M.R. Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential. Int. J. Mol. Sci. 2022, 23, 13280. https://doi.org/10.3390/ijms232113280
Stradiotto E, Allegrini D, Fossati G, Raimondi R, Sorrentino T, Tripepi D, Barone G, Inforzato A, Romano MR. Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential. International Journal of Molecular Sciences. 2022; 23(21):13280. https://doi.org/10.3390/ijms232113280
Chicago/Turabian StyleStradiotto, Elisa, Davide Allegrini, Giovanni Fossati, Raffaele Raimondi, Tania Sorrentino, Domenico Tripepi, Gianmaria Barone, Antonio Inforzato, and Mario R. Romano. 2022. "Genetic Aspects of Age-Related Macular Degeneration and Their Therapeutic Potential" International Journal of Molecular Sciences 23, no. 21: 13280. https://doi.org/10.3390/ijms232113280