作者：Jacquelyn K. Beals, PhD
出處：WebMD醫學新聞
September 2, 2008 — 中國和美國多個研究機構的研究者，辨識出一種可以避免地圖狀萎縮的基因變化，這個變化可以藉由抑制視網膜中的色素上皮細胞死亡，而避免地圖狀萎縮(geographic atrophy)。
地圖狀萎縮是乾性老年黃斑病變(AMD)的末期，造成10%的AMD致盲案例；資深作者、加州大學聖地牙哥分校Shiley 眼科中心眼科與人類基因教授Kang Zhang博士在電話訪問中為Medscape Pathology & Lab Medicine介紹此疾病。
Zhang博士表示，乾性或者濕性黃斑病變通常不會同時發生，乾性會變成濕性，但是濕性不會變成乾性，偶爾兩種都有，但是相當相當罕見；根據定義，地圖狀萎縮是乾性黃斑病變最嚴重的型態。
有越來越多證據認為AMD可能是因為細菌和病毒引起的發炎所導致，細菌的內毒素受體、類鐸受體4 (TLR4)基因變化之前被認為與AMD有關；發表於8月27日新英格蘭醫學期刊線上版的新研究，探討AMD和類鐸受體3(TLR3)變化之間的關聯，TLR3基因代表免疫防禦的病毒感受功能；有保護力的變化是該基因的412位置由 phenylalanine (Phe)替代leucine (Leu)。
該研究的分支之一探討TLR3變化和培養皿中人類視網膜色素上皮細胞生存力之間的關聯，後續治療以合成的雙股RNA(dsRNA)分子活化TLR3，和細胞Leu-Phe異合子相比，細胞Leu同合子者發生比較多的細胞凋亡(P = .02)。
研究者也評估脈絡膜新生血管(濕性AMD; n = 441)、地圖狀萎縮(n = 232)與早期到中期 AMD (n = 152)和控制組(n = 359)病患之TLR3 變化，結果發現Phe變化和避免地圖狀萎縮之間有顯著關聯(P = .005; 勝算比[OR] 於Leu/Phe 病患為 0.712; 95%信心區間[CI], 0.503 – 1.00; OR 於Phe/Phe病患為0.437; 95% CI, 0.227 – 0.839)；TLR3 變化在濕性或者早期到中期 AMD之間顯示沒有顯著關聯。
在地圖狀萎縮(n = 271) 、脈絡膜新生血管 (n = 179)與控制組(n = 421)病患中進行再現試驗，發現同樣的變化和地圖狀萎縮有顯著關聯(P =5.43 × 10-4) ，但是與脈絡膜新生血管無關；另外的案例控制再現試驗也顯示有同樣的關聯(P = .002)。
作者認為，活化TLR3 病毒dsRNA受體會造成視網膜色素上皮細胞從一開始的區域到鄰近區域漸漸發生地圖狀萎縮，可能之一為，病毒dsRNA受體受到乾的或者損傷的鄰近細胞所活化；另一個可能是，細胞之間的病毒顆粒傳播或者轉譯而活化受體。
Zhang博士指出，我們未確認一個特定的雙股病毒，但是一般而言如果你傷風感冒，你就曝露於dsRNA 病毒；鼻病毒、副流行性感冒病毒、流行性感冒病毒都是 dsRNA 病毒；無疑地，我們都曝露在dsRNA 病毒，不過，這是否是造成這些基因病患的死亡的原因之一，我們還不知道。
這個可能性增加了使用RNA干擾(短干擾RNA(siRNA)來不活化致病基因以治療濕性AMD之新治療的考量，以RNA干擾治療病患可以誘發TLR3 受體而導致地圖狀萎縮。
Zhang博士表示，它是病毒、siRNA或者類似分子並不重要，如果它可以活化TLR3而導致細胞凋亡，理論上就可能會引起地圖狀萎縮，不過，他指出，你知道只有少數人會獲得 siRNA，但是有許多人可以獲得dsRNA病毒。
Medscape Pathology & Lab Medicine也連絡David M. Brown醫師進行評論，Brown醫師執業於德州休士頓衛理教會醫院、玻璃體視網膜顧問、大休士頓視網膜研究中心；他表示，TLR3 受體設計上並沒有很非特定性，理論上任何非內生性RNA都可以啟動它。
如果是基因圖譜篩檢AMD以確認適當治療，Brown醫師提出他的看法，如果普及的話它會變成比較容易和相對上便宜，不過，它實際上還未有所幫助，除非在給予病患siRNA 藥物之前，先諮商有關地圖狀萎縮風險以及進行可能的篩檢。
Brown醫師表示，雖然我們的研究中心參與許多siRNA 第1期和第1-2期試驗，但我們不願意因為目前這個報告而在任何未來的siRNA試驗納入任何病患，因為siRNA有可能增加一些病患的地圖狀萎縮，這是相當恐怖的，除非證明這不會發生於人類眼中，納入持續中siRNA試驗的病患必須知道這個治療的可能影響，且密切追蹤地圖狀萎縮。
Zhang博士報告擁有Navigen的股權，且接受Genentech的資金和講課費用、接受Acucela 和Oxigene的顧問費用；Brown醫師報告參與許多siRNA治療試驗，同時擔任Genentech、Regeneron、Novartis、Allergan、Pfizer和Alcon等藥廠的顧問。
Gene Variant Protects Against Geographic Atrophy in Macular Degeneration
By Jacquelyn K. Beals, PhD
Medscape Medical News
September 2, 2008 — A gene variant that protects against geographic atrophy has been identified by investigators from several institutions in China and the United States. The variant appears to protect against geographic atrophy by suppressing the death of pigment epithelial cells in the retina.
Geographic atrophy, an advanced stage of dry age-related macular degeneration (AMD), causes 10% of the cases of blindness resulting from AMD. Senior author Kang Zhang, MD, PhD, professor of ophthalmology and human genetics, Shiley Eye Center, University of California –San Diego, La Jolla, described the disease to Medscape Pathology and Lab Medicine in a telephone interview.
"The wet or dry [macular degeneration]...usually do not happen together. So wet can come from dry, but dry does not come from wet.... Occasionally you have both, but it's very, very rare," said Dr. Zhang. "Geographic atrophy, by definition, is the most severe form of dry macular degeneration."
There is increasing evidence that AMD susceptibility is driven by inflammation provoked by bacteria and viruses. Variants of the toll-like receptor 4 gene (TLR4), a receptor for bacterial endotoxins, have previously been associated with AMD. The new study, published online August 27 in the New England Journal of Medicine, investigated the association between AMD and variants of toll-like receptor 3 (TLR3), a gene that codes for a viral sensor that functions in immunity and defense. The protective variant substitutes phenylalanine (Phe) for leucine (Leu) at position 412 of the gene product.
One branch of the study investigated the association between TLR3 variants and the viability of human retinal pigment epithelial cells in culture. Following treatment with a synthetic double-stranded RNA (dsRNA) molecule that activates TLR3, apoptosis occurred in more cells homozygous for the Leu form of the protein than in cells heterozygous for Leu-Phe (P = .02).
The investigators also assessed TLR3 variants in patients with choroidal neovascularization (wet AMD; n = 441), geographic atrophy (n = 232), and early-to-intermediate AMD (n = 152), as well as control patients (n = 359). A significant association was found between the Phe variant and protection against geographic atrophy (P = .005; odds ratio [OR] in Leu/Phe patients, .712; 95% confidence interval [CI], .503 – 1.00; OR in Phe/Phe patients, .437; 95% CI, .227 – .839). The TLR3 variants showed no significant association with wet or early-to-intermediate AMD.
Replications in patients with geographic atrophy (n = 271) and choroidal neovascularization (n = 179), as well as control patients (n = 421), found a significant association between the same variant and geographic atrophy (P = 5.43 × 10?4) but not choroidal neovascularization. An additional case-control replication demonstrated the same association (P = .002).
The authors suggest that activation of the TLR3 viral dsRNA receptor may underlie the progression of geographic atrophy from the initial region to adjacent areas of the retinal pigment epithelium. One possibility is that the viral dsRNA receptor is activated by RNA from dying or damaged adjacent cells. Another possibility is that cell-to-cell transmission of viral particles or transcripts may activate the receptor.
Dr. Zhang noted: "We haven't identified a specific double-stranded virus, but in general...if you have been having common colds, which all of us have, you are exposed to dsRNA viruses. Rhinovirus, parainfluenza virus, influenza virus are all dsRNA viruses. There's no question that we are all exposed to the dsRNA virus. However, if this is the one that actually causes cell death in the genetically susceptible patients, we don't know."
This possibility raises concerns about a new treatment for wet AMD that uses RNA interference (small interfering RNA; siRNA) to inactivate disease-causing genes. Treating a susceptible patient with RNA interference might trigger the TLR3 receptor and lead to geographic atrophy.
"It doesn't matter if it's viral, siRNA, or some similar molecule, if it can activate TLR3 that leads to apoptosis, that should be able in theory to cause geographic atrophy," said Dr. Zhang. However, he added, "you know, there's only very few people that are going to get siRNA, but a lot of people are going to get dsRNA viruses."
Medscape Pathology and Lab Medicine also contacted David M. Brown, MD, FACS, for comments. Dr. Brown is in practice at Greater Houston Retina Research, Vitreoretinal Consultants, The Methodist Hospital, Houston, Texas. "TLR3 receptors are by design very nonspecific," he said. "Theoretically...any nonendogenous RNA could potentially turn it on."
In terms of genotyping screens for AMD to determine the appropriate treatment, Dr. Brown expressed some concerns: "It would be easy and relatively cheap if it became commonplace. However, it really wouldn't be that helpful except for counseling [about] risk of geographic atrophy and potentially to screen prior to giving a patient an siRNA drug," he said.
"Although our research center was involved in several siRNA phase 1 and 1-2 trials, we would be reluctant to enroll any patients in any future siRNA trials given this current report.... The implications that the siRNA could potentially increase geographic atrophy in susceptible patients [are] very scary," observed Dr. Brown. "Unless this process is proven not to occur in human eyes, patients enrolled in continuing siRNA trials need to know the possible implications of this therapy and be followed closely for geographic atrophy."
Dr. Zhang reports having an equity interest in Navigen and has received grant support and lecture fees from Genentech and consulting fees from Acucela and Oxigene. Dr. Brown reports having participated in several siRNA therapeutic trials, and he has served as a consultant for Genentech, Regeneron, Novartis, Allergan, Pfizer, and Alcon.
N Engl J Med. 2008;359. Published online August 27, 2008.
[ 本帖最後由 goodcat1111 於 2008-9-12 00:02 編輯 ] |
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