OTOF基因突变听神经病的基因治疗临床试验与设计

钟佳珂;蒋罗颖;崔冲;韩双;陈玉鑫;韩磊;王大奇;陈兵;王武庆;李华伟;舒易来

1:复旦大学附属眼耳鼻喉科医院耳鼻喉科

2:国家卫生健康委员会听觉医学重点实验室

摘要
<正>目前,基因治疗是根治遗传性聋最有希望和最理想的策略之一,也是近年来全球听觉领域研究的重点、难点以及前沿热点。这在一定程度上得益于内耳独特的解剖结构——深埋于颞骨之中,其内充满内、外淋巴液,空间相对封闭,天然的血迷路屏障可使注入耳蜗的药物在局部随着淋巴液保持高浓度,同时最大限度地减少全身分布,降低非靶向器官和组织的可能风险。目前遗传性聋的基因治疗手段主要通过腺相关病毒(adeno-associated virus,AAV)载体向内耳递送具有正常功能的基因编码序列或基因编辑体系(如CRISPR/Cas9),以替代或纠正基因缺陷或异常,从而从根本上恢复患者的听力。
关键词
基金项目(Foundation):
国家杰出青年科学基金项目(82225014);; 国家重点研发计划合成生物学重点专项(2020YFA0908201);; 上海市2021年度“科技创新行动计划”生物医药科技支撑专项(21S11905100);; 上海市科学技术委员会“科技创新行动计划”细胞与基因治疗专项(23J31900100)
作者
钟佳珂;蒋罗颖;崔冲;韩双;陈玉鑫;韩磊;王大奇;陈兵;王武庆;李华伟;舒易来
参考文献

[1] ZHANG Q J,HAN B,LAN L,et al.High frequency of OTOF mutations in Chinese infants with congenital auditory neuropathy spectrum disorder[J].Clinical Genetics,2016,90(3):238-246.

[2] 韩磊,汤洪海,王大奇,等.OTOF基因突变听神经病的治疗进展[J].中国眼耳鼻喉科杂志,2023,23(2):117-122.

[3] FORLI F,CAPOBIANCO S,BERRETTINI S,et al.Temperature-sensitive auditory neuropathy:report of a novel variant of OTOF Gene and review of current literature[J].Medicina,2023,59(2):352.

[4] AKIL O,DYKA F,CALVET C,et al.Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model[J].ProcNatl Acad Sci USA,2019,116(10):4496-4501.

[5] LANDEGGER L D,PAN B,ASKEW C,et al.A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear[J].Nat Biotechnol,2017,35(3):280-284.

[6] AL-MOYED H,CEPEDA A P,JUNG S,et al.A dual-AAV approach restores fast exocytosis and partially rescues auditory function in deaf otoferlin knock-out mice[J].EMBO Mol Med,2019,11(1):e9396.

[7] ZHANG L,WANG H,XUN M,et al.Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and nonhuman primates[J].Mol Ther Methods ClinDev,2023,31:101154.

[8] TANG H,WANG H,WANG S,et al.Hearing of Otof-deficient mice restored by trans-splicing of N-and C-terminal otoferlin[J].Human Genetics,2023,142(2):289-304.

[9] WANG H,XUN M,TANG H,et al.Hair cell-specific Myo15 promoter-mediated gene therapy rescues hearing in DFNB9 mouse model[J].Mol Ther Nucleic Acids,2024,35(1):102135.

[10] HU S W,LV J,WANG Z,et al.Engineering of the AAV-compatible hair cell-specific small-size Myo15 promoter for Gene therapy in the inner ear[J].Research,2024,7:0341.

[11] RRG-003AAV治疗DFNB9先天性耳聋的安全性、耐受性及初步疗效研究[EB/OL].中国临床试验注册中心,(2022-09-01).https://www.chictr.org.cn/showproj.html?proj=194989.

[12] An Investigator Initiated Study for OTOV101N+OTOV101C Injection[EB/OL].ClinicalTrials.gov,(2023-5-9).https://classic.clinicaltrials.gov/show/NCT05901480.

[13] Gene Therapy Trial for Otoferlin Gene-Mediated Hearing Loss[EB/OL].ClinicalTrials.gov,(2023-2-8).https://classic.clinicaltrials.gov/show/NCT05821959.

[14] A Study of DB-OTO,an AAV Based Gene Therapy,in Children/Infants With Hearing Loss Due to Otoferlin Mutations (CHORD)[EB/OL].Clinical Trials.gov,(2023-3-15).https://classic.clinicaltrials.gov/show/NCT05788536.

[15] A Phase I/II Clinical Trial With SENS-501 in Children Suffering From Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations (AUDIOGENE)[EB/OL].Clinical Trials Information System,(2023-7-18).https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2023-504466-28-00

[16] LV J,WANG H,CHENG X,et al.AAV1-hOTOF gene therapy for autosomal recessive deafness 9:a single-arm trial[J].The Lancet,2024.DOI:10.1016/S0140-6736(23)02874-X.

[17] WANG H,CHEN Y,LV J,et al.Bilateral gene therapy in children with autosomal recessive deafness 9:single-arm trial results[J].Nat Med,2024,30(7):1898-1904.

[18] QI J,ZHANG L,TAN F,et al.Preclinical efficacy and safety evaluation of AAV-OTOF in DFNB9 mouse model and nonhuman primate[J].Advanced Science,2024,11(3):2306201.

[19] QI J,TAN F,ZHANG L,et al.AAV-mediated gene therapy restores hearing in patients with DFNB9 deafness[J].Advanced Science,2024:2306788.

[20] ANDRES-MATEOS E,LANDEGGER L D,UNZU C,et al.Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate[J].Nature Communications,2022,13(1):1359.

[21] VONA B,RAD A,REISINGER E.The many faces of DFNB9:relating OTOF variants to hearing impairment[J].Genes (Basel),2020,11(12):1411.

[22] WEI? C,ZIEGLER A,BECKER L L,et al.Gene replacement therapy with onasemnogeneabeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg:an observational cohort study[J].Lancet Child Adolesc Health,2022,6(1):17-27.

[23] FINKEL R S,CHIRIBOGA C A,VAJSAR J,et al.Treatment of infantile-onset spinal muscular atrophy with nusinersen:final report of a phase 2,open-label,multicentre,dose-escalation study[J].Lancet Child Adolesc Health,2021,5(7):491-500.

[24] DAY J W,FINKEL R S,CHIRIBOGA C A,et al.Onasemnogeneabeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE):an open-label,single-arm,multicentre,phase 3 trial[J].Lancet Neurol,2021,20(4):284-293.

[25] MERCURI E,VILCHEZ J J,BOESPFLUG-TANGUY O,et al.Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS):a multicentre,randomised,double-blind,placebo-controlled,phase 3 trial[J].Lancet Neurol,2024,23(4):393-403.

[26] HOY S M.Delandistrogene moxeparvovec:first approval[J].Drugs,2023,83(14):1323-1329.

[27] RANGARAJAN S,WALSH L,LESTER W,et al.AAV5-factor VIII gene transfer in severe hemophilia A[J].N Engl J Med,2017,377(26):2519-2530.

[28] KOHN D B,BOOTH C,SHAW K L,et al.Autologous ex vivo lentiviral gene therapy for adenosine deaminase deficiency[J].N Engl J Med,2021,384(21):2002-2013.

[29] FLANIGAN K M,VETTER T A,SIMMONS T R,et al.A first-in-human phase I/IIa gene transfer clinical trial for Duchenne muscular dystrophy using rAAVrh74.MCK.GALGT2[J].Mol Ther Methods Clin Dev,2022,27:47-60.

[30] 王秋菊.新医学时代遗传性聋研究与应用[J].听力学及言语疾病杂志,2023,31(3):197-201.

[31] 舒易来,范新泰,高子雯,等.遗传性耳聋基因治疗专家共识(2023,上海)[J].中国眼耳鼻喉科杂志,2024,24(1):1-6.

[32] NIST-LUND C A,PAN B,PATTERSON A,et al.Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders[J].Nat Commun,2019,10(1):236.

[33] WU J,SOLANES P,NIST-LUND C,et al.Single and dual vector gene therapy with AAV9-PHP.B rescues hearing in tmc1 mutant mice[J].Mol Ther,2021,29(3):973-988.

[34] YEH W H,SHUBINA-OLEINIK O,LEVY J M,et al.In vivo base editing restores sensory transduction and transiently improves auditory function in a mouse model of recessive deafness[J].Sci Transl Med,2020,12(546):eaay9101.

[35] SHUBINA-OLEINIK O,NIST-LUND C,FRENCH C,et al.Dual-vector gene therapy restores cochlear amplification and auditory sensitivity in a mouse model of DFNB16 hearing loss[J].Sci Adv,2021,7(51):eabi7629.

[36] LENTZ J J,PAN B,PONNATH A,et al.Direct delivery of antisense oligonucleotides to the middle and inner ear improves hearing and balance in Usher mice[J].Mol Ther,2020,28(12):2662-2676.

[37] PONNATH A,DEPREUX F F,JODELKA F M,et al.Rescue of outer hair cells with antisense oligonucleotides in Usher mice is dependent on age of treatment[J].J Assoc Res Otolaryngo,2018,19(1):1-16.

[38] XUE Y,HU X,WANG D,et al.Gene editing in a Myo6 semi-dominant mouse model rescues auditory function[J].Mol Ther,2022,30(1):105-118.

[39] NOH B,RIM J H,GOPALAPPA R,et al.In vivo outer hair cell gene editing ameliorates progressive hearing loss in dominant-negative Kcnq4 murine model[J].Theranostics,2022,12(5):2465-2482.

[40] 吴玉森,王秋菊.USH2综合征型耳聋的基因型与表型特征研究进展[J].听力学及言语疾病杂志,2019,27(5):548-555.

[41] STEMERDINK M,GARCíA-BOHóRQUEZ B,SCHELLENS R,et al.Genetics,pathogenesis and therapeutic developments for Usher syndrome type 2[J].Hum Genet,2022,141(3-4):737-758.

[42] HIGH K A,RONCAROLO M G.Gene therapy[J].N Engl J Med,2019,381(5):455-464.