MUT型甲基丙二酸血症基因治疗研究进展

doi:10.12372/jcp.2024.24e0274

摘要/Abstract

摘要：

MUT型甲基丙二酸血症（MMA）是由MMUT基因变异引起的常染色体隐性遗传病，可涉及多脏器损害，以脑损伤为主，死亡率较高。MUT型MMA目前治疗主要包括饮食治疗、左卡尼汀及维生素B₁₂药物治疗，部分严重患者需要肝肾移植，但上述治疗效果不佳，患者预后较差。近几年，在MUT型MMA小鼠模型中已利用腺病毒载体、慢病毒载体、基因编辑、mRNA非病毒载体进行基因治疗及Ⅰ/Ⅱ期临床试验。目前相关临床试验尚处于研发早期，基因治疗有望成为MUT型MMA新治疗方法。文章对MUT型MMA基因治疗研究现状进行系统总结，为后续研究提供参考。

关键词: 甲基丙二酸血症, MMUT基因, 基因治疗

Abstract:

MUT-type methylmalonic acidemia (MMA) is an autosomal monogenic genetic disorder caused by mutations in the MMUT gene, which can involve multiple organ damage, mainly brain damage, and has a high mortality rate. Diet therapy, levocarnitine and vitamin B₁₂ therapy are the main treatment method for MUT-type MMA, and some severe patients need liver and kidney transplantation, but the treatment effect and prognosis are poor. Gene therapy for MUT-type MMA using various vectors in animal model and phase 1/2 study are underway. Gene therapy in MUT-type MMA clinical trials is still in an early stage and provides a new treatment method. This article reviews the current status of gene therapy research for MUT-type MMA and aims to guide future research.

Key words: methylmalonic acidemia, MMUT gene, gene therapy

丁一, 于玥, 韩连书. MUT型甲基丙二酸血症基因治疗研究进展[J]. 临床儿科杂志, 2024, 42(12): 1051-1055.

Reviewer: DING Yi, YU Yue, Reviser: HAN Lianshu. Research progress in gene therapy for MUT-type methylmalonic acidemia[J]. Journal of Clinical Pediatrics, 2024, 42(12): 1051-1055.

参考文献 33

[1]	Acquaviva C, Benoist JF, Pereira S, et al. Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene[J]. Hum Mutat, 2005, 25(2): 167-176. pmid: 15643616
[2]	杨艳玲, 韩连书. 单纯型甲基丙二酸尿症饮食治疗与营养管理专家共识[J]. 中国实用儿科杂志, 2018, 33(7): 481-486.
[3]	Jiang YZ, Sun LY. The value of liver transplantation for methylmalonic acidemia[J]. Front Pediatr, 2019, 7: 87.
[4]	High KA, Roncarolo MG. Gene therapy[J]. N Engl J Med, 2019, 381(5): 455-464.
[5]	Ramamoorth M, Narvekar A. Non viral vectors in gene therapy- an overview[J]. J Clin Diagn Res, 2015, 9(1): Ge01- Ge06.
[6]	Chandler RJ, Tsai MS, Dorko K, et al. Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes[J]. BMC Med Genet, 2007, 8: 24. pmid: 17470278
[7]	Peters H, Nefedov M, Sarsero J, et al. A knock-out mouse model for methylmalonic aciduria resulting in neonatal lethality[J]. J Biol Chem, 2003, 278(52): 52909-52913. doi: 10.1074/jbc.M310533200 pmid: 14555645
[8]	Chandler RJ, Venditti CP. Genetic and genomic systems to study methylmalonic acidemia[J]. Mol Genet Metab, 2005, 86(1-2): 34-43. pmid: 16182581
[9]	Chandler RJ, Venditti CP. Adenovirus-mediated gene delivery rescues a neonatal lethal murine model of mut(0) methylmalonic acidemia[J]. Hum Gene Ther, 2008, 19(1): 53-60. doi: 10.1089/hum.2007.0118 pmid: 18052792
[10]	Zhong L, Granelli-Piperno A, Choi Y, et al. Recombinant adenovirus is an efficient and non-perturbing genetic vector for human dendritic cells[J]. Eur J Immunol, 1999, 29(3): 964-972. pmid: 10092101
[11]	Gao G, Vandenberghe LH, Alvira MR, et al. Clades of adeno-associated viruses are widely disseminated in human tissues[J]. J Virol, 2004, 78(12): 6381-6388. pmid: 15163731
[12]	Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene therapy[J]. Mol Ther, 2006, 14(3): 316-327. doi: 10.1016/j.ymthe.2006.05.009 pmid: 16824801
[13]	Chandler RJ, Venditti CP. Long-term rescue of a lethal murine model of methylmalonic acidemia using adeno-associated viral gene therapy[J]. Mol Ther, 2010, 18(1): 11-16. doi: 10.1038/mt.2009.247 pmid: 19861951
[14]	Carrillo-Carrasco N, Chandler RJ, Chandrasekaran S, et al. Liver-directed recombinant adeno-associated viral gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction[J]. Hum Gene Ther, 2010, 21(9): 1147-1154. doi: 10.1089/hum.2010.008 pmid: 20486773
[15]	Senac JS, Chandler RJ, Sysol JR, et al. Gene therapy in a murine model of methylmalonic acidemia using rAAV9-mediated gene delivery[J]. Gene Ther, 2012, 19(4): 385-391. doi: 10.1038/gt.2011.108 pmid: 21776024
[16]	Chandler RJ, Venditti CP. Pre-clinical efficacy and dosing of an AAV8 vector expressing human methylmalonyl-CoA mutase in a murine model of methylmalonic acidemia (MMA)[J]. Mol Genet Metab, 2012, 107(3): 617-619. doi: 10.1016/j.ymgme.2012.09.019 pmid: 23046887
[17]	Manoli I, Sysol JR, Epping MW, et al. FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia[J]. JCI Insight, 2018, 3(23): e124351.
[18]	Manoli I, Sysol J, Li L, et al. Muscle targeted transgene expression rescues the lethal phenotype of Mut knockout mice[C]. 34th Annual Meeting of the Society-for-Inherited-Metabolic-Disorders. 2011.
[19]	Mingozzi F, High KA. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape[J]. Annu Rev Virol, 2017, 4(1): 511-534. doi: 10.1146/annurev-virology-101416-041936 pmid: 28961410
[20]	Chandler RJ, Di Pasquale G, Sloan JL, et al. Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9[J]. Mol Ther Methods Clin Dev, 2022, 27: 61-72.
[21]	Kishimoto TK. Development of ImmTOR tolerogenic nanoparticles for the mitigation of anti-drug antibodies[J]. Front Immunol, 2020, 11: 969. doi: 10.3389/fimmu.2020.00969 pmid: 32508839
[22]	Ilyinskii PO, Michaud AM, Rizzo GL, et al. ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia[J]. Mol Ther Methods Clin Dev, 2021, 22: 279-292.
[23]	Marshall H M, Ronen K, Berry C, et al. Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting[J]. PLoS One, 2007, 2(12): e1340. doi: 10.1371/journal.pone.0001340 pmid: 18092005
[24]	Wong ES, McIntyre C, Peters HL, et al. Correction of methylmalonic aciduria in vivo using a codon-optimized lentiviral vector[J]. Hum Gene Ther, 2014, 25(6): 529-538. doi: 10.1089/hum.2013.111 pmid: 24568291
[25]	Peters HL, Pitt JJ, Wood LR, et al. Mouse models for methylmalonic aciduria[J]. PLoS One, 2012, 7(7): e40609.
[26]	Bulcha JT, Wang Y, Ma H, et al. Viral vector platforms within the gene therapy landscape[J]. Signal Transduct Target Ther, 2021, 6(1): 53.
[27]	罗小平, 应艳琴. 基因编辑与遗传代谢性疾病[J]. 中国儿童保健杂志, 2021, 29(7): 697-700. doi: 10.11852/zgetbjzz2021-0965
[28]	Barzel A, Paulk NK, Shi Y, et al. Promoterless gene targeting without nucleases ameliorates haemophilia B in mice[J]. Nature, 2015, 517(7534): 360-364.
[29]	Chandler RJ, Venturoni LE, Liao J, et al. Promoterless, nuclease-free genome editing confers a growth advantage for corrected hepatocytes in mice with methylmalonic acidemia[J]. Hepatology, 2021, 73(6): 2223-2237.
[30]	An D, Schneller JL, Frassetto A, et al. Systemic messenger RNA therapy as a treatment for methylmalonic acidemia[J]. Cell Rep, 2017, 21(12): 3548-3558. doi: S2211-1247(17)31748-5 pmid: 29262333
[31]	An D, Frassetto A, Jacquinet E, et al. Long-term efficacy and safety of mRNA therapy in two murine models of methylmalonic acidemia[J]. EBioMedicine, 2019, 45: 519-528. doi: S2352-3964(19)30438-4 pmid: 31303505
[32]	Loughrey D, Dahlman JE. Non-liver mRNA delivery[J]. Acc Chem Res, 2022, 55(1): 13-23.
[33]	Witzigmann D, Kulkarni JA, Leung y, et al. Lipid nanopaticle technology for therapeutic gene regulation in the liverlyl[J]. Ady Drug Deliy Rev, 2020(159): 344-363.