2013年4月25日訊 /生物谷BIOON/--華盛頓大學醫學院和麻薩諸塞州總院的科學家完成了治療遺傳性肌萎縮性脊髓側索硬化症（ALS）的一期臨床安全性試驗。
科學家顯示了該療法對ALS病人無嚴重副作用。一期臨床實驗的結果顯示了該療法有望治療患有中樞神經系統疾病的病人。相關報導發表在近期Lancet Neurology上。
該療法採用一種方法能夠關閉引起ALS的突變基因的表達。該療法之前從未在神經系統疾病中進行過嘗試治療。
該文章的通訊作者Timothy Miller博士稱，我們在治療ALS方面有了長足的進展，是時候考慮採用相同的方法治療其他神經系統疾病了。該方法有望能夠治療多種神經系統疾病，諸如AD，PD，HD和其他各種疾病。
ALS破壞控制肌肉的神經，逐步導致癱瘓以致死亡。唯一獲得FDA認證的治療藥物為Riluzole，而該藥的效果並不是特別明顯。
大多數的ALS是散發性的，但是大約10%的ALS是由於遺傳突變造成的。科學家已經發現了10個能夠引起該病的基因，並仍在尋找其他相關基因。
本研究集中在由於SOD1基因突變造成的ALS。該病因佔整體病人的2%。科學家已發現SOD1的一百個突變能夠引起ALS。
Miller博士稱，在分子水平，這些突變以不同方式改變SOD1蛋白的性質，但是都會引起ALS。
Miller博士和他的研究團隊致力於採用稱之為反轉錄療法的技術來阻斷SOD1蛋白的表達。Miller博士稱，反轉錄療法在過去數十年中已經用於多種疾病的治療，如FDA最近通過了一種稱之為Kynamro的反轉錄療法用於治療家族型高膽固醇血症。
Miller博士帶領的研究團隊已經開發出來針對SOD1的反轉錄藥物，並且在動物模型中成功的治療ALS。Miller博士與麻薩諸塞州總院的醫生合作進行了一期臨床實驗。該實驗對SOD1相關的ALS病人進行反轉錄療法治療。治療包括對病人進行11小時的脊髓輸液。科學家發現治療組和對照組相比沒有副作用。而頭痛和背痛是脊髓輸液最常見的副作用。
在輸液之後，科學家提取了脊髓液樣本，進一步確認該反轉錄藥物隨著脊髓液在病人體內循環。
為了進行二期臨床試驗，科學家將需要增加反轉錄藥物的劑量。隨著劑量上升，觀測該療法不會引起炎症反應或其他副作用。
Miller博士稱，我們現在得到的數據顯示降低SOD1的方法是安全的，事實上SOD1完全失活的小鼠看起來沒有副作用。我們相信在病人體內同樣適用，但是只有在之後的試驗中才能進一步證明這一點。（生物谷Bioon.com）
An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study.
Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME.
BACKGROUND: Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis. METHODS: In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222. FINDINGS: Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated. INTERPRETATION: This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. FUNDING: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.