vicky3

作者：Barbara Boughton  
出處：WebMD醫學新聞

　　October 26, 2009 (加州舊金山) — 在一篇戲劇化的第1期試驗中，基因治療改善了嚴重視網膜退化疾患、利伯氏先天性黑內障(Leber's congenital amaurosis，LCA)者的視力，且這改善在追蹤兩年後依舊穩定。
　　
　　根據美國眼科學院與泛美眼科協會聯合年會中發表的研究者指出，視力與光敏感的改變在小孩最明顯，可以在低亮度的障礙中找到方向。這篇第1期試驗的結果線上登載於10月23日的The Lancet期刊。
　　
　　資深研究者、賓州大學醫學院眼科教授Jean Bennett博士在Medscape Pathology and Lab Medicine的訪問中表示，我們發現全部研究對象都有效，但是年輕人的視力和光敏感性改善最多。這項資料相當令人鼓舞，也激勵我們開始嘗試以基因治療其他遺傳性眼盲。
　　
　　試驗的12名研究對象的年紀介於8到44歲，有4人介於8到11歲—接受基因治療非致命性疾病的最年輕個案。雖然病患並未恢復正常的視力，半數已經藉此改善而不再被歸類於眼盲。
　　
　　LCA的特徵是視力嚴重喪失，嬰幼童時期即出現眼球震顫且在30、40歲前惡化而眼盲。此病症是因為13個基因中的任一個發生突變所引起。該試驗研究的第2型LCA，是因為RPE65基因突變引起，佔所有案例的6%。
　　
　　研究中，正常功能的RPE65基因被嵌入一個病毒媒介，之後在手術中將這個媒介導入視網膜下方。第一作者、賓州大學眼科副教授、賓州兒童醫院醫師Albert Maguire解釋，這個修飾過、帶有健康RPE65基因的病毒進入患部細胞且修飾酵素缺陷。
　　
　　Maguire醫師和Bennett醫師等研究人員，自2000年開始以此方式檢測LCA的RPE65基因，他們最初是對3隻狗進行注射治療。Bennett醫師表示，幾個月之後牠們可以看見，我們相信這在人類也是個安全有效的好機會。
　　
　　2008年5月時，研究團隊在新英格蘭醫學期刊(New England Journal of Medicine) (2008;358:2240-2248)發表3個成人的第1期試驗初步結果，發現這些人的視力功能檢測有所改善。該試驗接著擴展到其他9個對象，對功能惡化的眼睛注射低、中、高劑量的治療。
　　
　　結果指出，12名病患在手術後兩週開始，全部在模糊環境中的視力都有所改善。3名接受低劑量的病患、3名接受中劑量的病患、1名接受高劑量病患的視力有顯著改善。有1名病患在治療後視力惡化。不過，12名病患的視野都有改善，瞳孔對光的反應與敏感度也有改善。7個人的眼球震顫有顯著改善。所有病患都沒有副作用。
　　
　　荷蘭Radboud大學Nijmegen醫學中心的Frans P.M. Cremers博士和Rob W.J. Collin博士在該期期刊的編輯評論中指出，該研究顯示，基因治療可顯著改善利伯氏先天性黑內障的視力，也有效延緩或停止視網膜色素變性患者的漸進式視網膜退化，這可使病患多保留許多年的視力。
　　
　　實際上，該報告的作者們已經開始對其他遺傳性眼疾進行基因治療的臨床前研究，包括視網膜色素變性以及其他類型的LCA。他們也將進行第3期試驗，他們希望在兩年內完成，目標是獲得美國食品藥物管理局核准該基因治療。
　　
　　波特蘭Casey眼科研究中心教授、奧勒剛健康與科學大學副總裁Tim Stout博士表示，目前的研究確定LCA與其他遺傳性視網膜眼疾之病童最可能受惠於基因治療，因為他們的細胞損傷比成人少。Stout博士主持一項有關第2型LCA之基因治療的試驗，但是使用不同的病毒媒介。
　　
　　他表示，我們全都同意及早治療病患—也就是在他們可以恢復更多視力功能的時候進行治療。我們需要確保這個治療是安全的，一旦完成，我們可以治療更年幼的小孩、甚至8歲以下都可以治療。
　　
　　Bennett醫師、 Maguire醫師、Cremers醫師、Collin醫師、Stout醫師皆宣告沒有相關財務關係。
　　
　　美國眼科學院與泛美眼科協會(AAO-PAAO)聯合年會。利伯氏先天性黑內障治療更新。發表於2009年10月24日。
　　
　　Lancet。線上發表於2009年10月23日。

Gene Therapy Improves Eyesight in Inherited Retinal Eye Disease

By Barbara Boughton
Medscape Medical News

October 26, 2009 (San Francisco, California) — In a dramatic phase?1 trial, gene therapy improved eyesight in people with one of the most severe forms of retinal degeneration, Leber's congenital amaurosis (LCA), and the improvements remained stable after 2 years of follow-up.

Changes in visual acuity and light sensitivity were most marked in children, who showed striking improvement in the ability to navigate a low-light obstacle course, according to researchers here at the American Academy of Ophthalmology Joint Annual Meeting With the Pan-American Association of Ophthalmology. The results of the phase?1 trial were also published online October 23 in The Lancet.

"We found efficacy in all subjects, but the most improvement in visual acuity and light sensitivity occurred in younger individuals," said senior researcher Jean Bennett, MD, PhD, who is the FM Kirby Professor of Ophthalmology at the University of Pennsylvania School of Medicine in Philadelphia, during an interview with Medscape Pathology and Lab Medicine. "The data are very encouraging and may jump start attempts to treat other inherited forms of blindness with gene therapy."

The 12 subjects in the trial ranged in age from 8 to 44 years, and 4 were between 8 and 11 years — the youngest individuals to receive gene therapy for a nonlethal disease. Although the patients did not regain normal eyesight, half of them improved enough so that they were no longer classified as legally blind.

LCA is marked by severe loss of vision and nystagmus that begins in early infancy and childhood and progresses to blindness by the third or fourth decade of life. The disorder is caused by mutations in any of 13 genes. Type?2 LCA, the form studied in the research trial, is caused by a mutation in the RPE65 gene, and accounts for about 6% of all cases.

In the study, a normal functioning RPE65 gene was spliced into a viral vector, and the vector was then injected into the subretinal space during surgery. "The modified virus piggybacks the healthy RPE65 gene into diseased cells and corrects the enzyme defect," explained lead author Albert Maguire, MD, associate professor of ophthalmology at Pennsylvania State University and a physician at the Children's Hospital of Philadelphia.

Drs. Maguire and Bennett and fellow researchers have been testing this approach with the RPE65 gene in LCA since 2000, when they first injected 3 dogs with the therapy. "A few months later they could see," Dr. Bennett said. "We became convinced that this would have a good chance for safety and efficacy in humans."

In May 2008, the research team published preliminary results of the phase?1 trial on 3 adults in the New England Journal of Medicine (2008;358:2240-2248), revealing that subjects showed improved function on vision tests. The trial was then extended to 9 other subjects, who received either a low, medium, or high dose of the therapy in the eye with the worst function at baseline.

Results indicated that all 12 patients reported improved vision in dimly lit environments beginning 2 weeks after surgery. Visual acuity improved significantly in 3 patients who received the low dose, 3 who received the medium dose, and 1 who received the high dose. In 1 patient, visual acuity worsened after treatment. However, visual field improved in all 12 patients, as did pupillary response and sensitivity to light. Seven had significant improvements in nystagmus. None experienced adverse events.

In an editorial accompanying The Lancet paper, Frans P.M. Cremers, PhD, and Rob W.J. Collin, PhD, from Radboud University Nijmegen Medical Centre in the Netherlands, noted that the study showed that "gene therapy might provide a major improvement of vision in patients with Leber's congenital amaurosis, and holds the promise that the progressive retinal degeneration in patients with retinitis pigmentosa can be slowed down or stopped, which would render the patients many more years of vision."

Indeed, the authors of the paper have already started preclinical studies of gene therapy in other inherited eye diseases, including retinitis pigmentosa and other forms of LCA. They will also be moving forward with a phase?3 trial, which they hope to complete in 2 years, with the goal of obtaining licensing from the US Food ad Drug Administration for the gene therapy treatment.

The current study conclusively shows that children with LCA and other inherited forms of retinal eye disorders are most likely to benefit from gene therapy because they have sustained less cellular damage than adults, said Tim Stout, MD, PhD, vice president of Oregon Health Science University and professor at the Casey Eye Institute in Portland. Dr. Stout is heading a gene therapy trial treating patients with type?2 LCA, but using a different viral vector.

"We can all agree that treating patients earlier is probably a smart idea — at a stage where they can recover more visual function," he said. "We need to make sure this therapy is safe, but once we've done that, we can move toward treating younger and younger children, even children younger than 8 years old," he said.

Dr. Bennett, Dr. Maguire, Dr. Cremers, Dr. Collin, and Dr. Stout have disclosed no relevant financial relationships.

American Academy of Ophthalmology Joint Annual Meeting With the Pan-American Association of Ophthalmology (AAO-PAAO). Leber Congenital Amaurosis Therapy Update. Presented October 24, 2009.

Lancet. Published online October 23, 2009.