Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients

被引:12
作者
Magen, Iddo [1 ,2 ]
Aharoni, Sharon [3 ,4 ]
Yacovzada, Nancy Sarah [1 ,2 ]
Latzer, Itay Tokatly [4 ,5 ]
Alves, Christiano R. R.
Sagi, Liora [4 ,5 ]
Fattal-Valevski, Aviva [4 ,5 ]
Swoboda, Kathryn J. [6 ]
Katz, Jacob [4 ,7 ]
Bruckheimer, Elchanan [4 ,8 ]
Nevo, Yoram [3 ,4 ]
Hornstein, Eran [1 ,2 ]
机构
[1] Weizmann Inst Sci, Dept Mol Genet, Rehovot, Israel
[2] Weizmann Inst Sci, Dept Mol Neurosci, Rehovot, Israel
[3] Schneider Childrens Med Ctr Israel, Inst Pediat Neurol, Petah Tiqwa, Israel
[4] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel
[5] Tel Aviv Med Ctr & Sch Med, Pediat Neurol Inst, Dana Dwek Childrens Hosp, Tel Aviv, Israel
[6] Massachusetts Gen Hosp, Dept Neurol, Ctr Genom Med, Boston, MA USA
[7] Schneider Childrens Med Ctr Israel, Div Dept Anesthesia, Petah Tiqwa, Israel
[8] Schneider Childrens Med Ctr Israel, Cardiol Inst, Petah Tiqwa, Israel
基金
以色列科学基金会; 欧洲研究理事会;
关键词
Biomarkers; Cerebrospinal Fluid; miR-206; miR-133; Muscle microRNAs; Nusinersen; Response predictors; Spinal muscular atrophy; SHAM CONTROL; ONSET; BIOMARKER; PROLIFERATION; CHILDHOOD; CHILDREN; MIR-206;
D O I
10.1111/ene.15382
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Background and purpose: The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. Methods: Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by >= 3 or <= 0 points in the HFMSE total score were considered to be responders or nonresponders, respectively. Results: Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a- 3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. Conclusions: Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.
引用
收藏
页码:2420 / 2430
页数:11
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