Dry age-related macular degeneration (AMD) is a blinding disease that affects about 7.4 Million individuals in Germany. Researchers at the Paul-Ehrlich-Institut as part of an international consortium have uncovered a mechanism that is based on the activation of mobile genetic elements (retrotransposons) in the genome and leads to damage and death of cells of the retina in patients suffering from dry AMD.
A meta-analysis of health insurance data was carried out, confirming these findings, because treatment with drugs known to inhibit the activity of mobile element-encoded enzymes reduce the number of persons developing dry AMD. PNAS reports on these results in its online edition of 01 February 2021.
Left: Healthy retinal pigment epithelium (RPE); right: RPE in which Alu RNA has been expressed. Destruction of contiguous cellular membrane structures is visible (Source: Gerald G. Schumann / Paul-Ehrlich-Institut). Left: Healthy retinal pigment epithelium (RPE); right: RPE in which Alu RNA has been expressed. Destruction of contiguous cellular membrane structures is visible.
As part of an international research collaboration, coordinated by Dr J. Ambati, University of Virginia, Charlottesville, VA, USA, and Dr. F. Gage, Salk Institute for Biological Studies, La Jolla, CA, USA, the research team led by Dr. G. Schumann, Division of Medical Biotechnology at the Paul-Ehrlich-Institut, have found the causal mechanism for the so-called geographic atrophy of dry AMD. In this process, the cells of the retinal pigment epithelium (RPE), essential for the ability to see, die, which can lead to blindness.
The international research team could show that in the case of dry AMD, DNA (Deoxyribonucleic acid) of so called transposable Alu elements accumulated in the cytoplasm of cells of the retinal pigment epithelium (RPE). Transposable elements (TEs) are mobile genomic DNA fragments that can spread throughout the genome of individual cells.
Accumulation of Alu DNA was demonstrated to occur by transcription of Alu RNA into Alu DNA in the cytoplasm of these cells by proteins encoded by LINE1 elements, another group of TEs. The accumulated Alu DNA damages the cells that finally die – the consequence is geographic atrophy, the advanced vision-threatening form of AMD.
The researchers also succeeded in unravelling the mechanism responsible for rewriting Alu RNA into DNA. The results demonstrate for the first time that Alu RNA can be reverse transcribed into DNA in the cytoplasm of the host cell by host-encoded enzymes. There is no evidence that this Alu DNA is transferred into the nucleus and/or subsequently integrated into the genome.
Based on these new findings indicating that TE activity is responsible for vision loss at a later stage of AMD, drugs already used to treat patients with HIV (Human Immunodeficiency Virus) infections, became the focus of interest. These drugs inhibit HIV-1 reverse transcriptase which is the enzyme rewriting HIV RNA into DNA.
In fact, these medicines, which are called nucleoside reverse transcriptase inhibitors (NRTIs), also inhibit the activity of the reverse transcriptase, which is responsible for rewriting Alu RNA into DNA.
The analysis of four databases of different health insurance companies in the USA, in which more than 100 million patients were enrolled over a period of 20 years confirm that these medicines could constitute a promising therapeutic approach against dry AMD: individuals treated with NRTIs were almost 40% less likely to develop dry macular degeneration.
Preparations for first clinical trials for the use of NRTIs or their, more tolerable, derivatives known as Kamuvudines have already been initiated.
Fukuda S, Varshney A, Fowler BJ, Wang S, Narendran S, Ambati K, Yasuma T, Magagnoli J, Leung H, Hirahara S, Nagasaka Y, Yasuma R, Apicella I, Pereira F, Makin RD, Magner E, Liu X, Sun J, Wang M, Baker K, Marion KM, Huang X, Baghdasaryan E, Ambati M, Ambati VL, Pandey A, Pandya L, Cummings T, Banerjee D, Huang P, Yerramothu P, Tolstonog GV, Held U, Erwin JA, Paquola ACM, Herdy JR, Ogura Y, Terasaki H, Oshika T, Darwish S, Singh R, Mozaffari S, Bhattarai D, Kim KY, Hardin JW, Bennett CL, Hinton DR, Hanson TE, Röver C, Parang K, Kerur N, Liu J, Werner BC, Sutton SC, Sadda SR, Schumann GG, Gelfand BD, Gage FH, Ambati J (2021): Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.
The Paul-Ehrlich-Institut is an Agency of the German Federal Ministry of Health.
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