基于mRNA的蛋白替代疗法对于遗传代谢性疾病的治疗研究进展
Research Progress on mRNA Based Protein Replacement Therapy for Inborn Errors of Metabolism
DOI: 10.12677/acm.2025.154899, PDF,   
作者: 李京蔚, 包茂蓉, 宋 萃*：重庆医科大学附属儿童医院内分泌科，国家儿童健康与疾病临床医学研究中心，儿童发育疾病研究教育部重点实验室，重庆
关键词: mRNA治疗；罕见病；遗传代谢性疾病；蛋白替代疗法；mRNA Therapy； Rare Diseases； Inborn Errors of Metabolism； Protein Replacement Therapy
摘要: 罕见病又称孤儿病，由于其单病种发病率低，因此往往缺乏有效的治疗手段，严重危害患者的身体健康，而遗传代谢性疾病(Inborn errors of metabolism, IEM)正是罕见病的重要组成部分。近年来由于信使RNA (mRNA)技术的发展，尤其是mRNA疫苗问世以后，基于mRNA的蛋白替代疗法逐渐成为了一种可行的治疗IEM的方法。其可以将经化学修饰的携带特定蛋白质信息的mRNA利用靶向递送技术导入宿主细胞，进而产生功能蛋白来修复缺陷的代谢通路，目前的动物试验及部分开展的临床试验已经证明了其具有生物相容性、精确剂量、瞬时表达和基因组整合风险最小等优点。本文将针对基于mRNA的蛋白替代疗法，并针对遗传代谢性疾病较为典型的氨基酸代谢障碍、有机酸代谢障碍以及尿素循环障碍相关疾病为例进行概述。
Abstract: Rare diseases, also known as orphan diseases, often lack effective treatment due to their low incidence rate of single disease, which seriously endangers the health of patients. Inborn errors of metabolism (IEM) are an important part of rare diseases. In recent years, due to the development of messenger RNA (mRNA) technology, especially after the emergence of mRNA vaccines, mRNA based protein replacement therapy has gradually become a feasible method for treating IEM. It can use targeted delivery technology to introduce chemically modified mRNA carrying specific protein information into host cells, thereby producing functional proteins to repair defective metabolic pathways. Current animal experiments and some clinical trials have demonstrated its advantages such as biocompatibility, precise dosage, transient expression, and minimal risk of genome integration. This article will focus on mRNA based protein replacement therapy and provide an overview of typical genetic metabolic disorders such as amino acid metabolism disorders, organic acid metabolism disorders, and urea cycle disorders.
文章引用：李京蔚, 包茂蓉, 宋萃. 基于mRNA的蛋白替代疗法对于遗传代谢性疾病的治疗研究进展[J]. 临床医学进展, 2025, 15(4): 35-43. https://doi.org/10.12677/acm.2025.154899

参考文献

[1] 宣兆宇. 串联质谱技术在新生儿遗传代谢性疾病筛查中的应用[J]. 中国妇幼保健, 2022, 37(17): 3290-3293.
[2] Shen, G., Liu, J., Yang, H., Xie, N. and Yang, Y. (2024) MRNA Therapies: Pioneering a New Era in Rare Genetic Disease Treatment. Journal of Controlled Release, 369, 696-721. [Google Scholar] [CrossRef] [PubMed]
[3] Bulcha, J.T., Wang, Y., Ma, H., Tai, P.W.L. and Gao, G. (2021) Viral Vector Platforms within the Gene Therapy Landscape. Signal Transduction and Targeted Therapy, 6, Article No. 53. [Google Scholar] [CrossRef] [PubMed]
[4] Granot-Matok, Y., Kon, E., Dammes, N., Mechtinger, G. and Peer, D. (2019) Therapeutic mRNA Delivery to Leukocytes. Journal of Controlled Release, 305, 165-175. [Google Scholar] [CrossRef] [PubMed]
[5] Rohner, E., Yang, R., Foo, K.S., Goedel, A. and Chien, K.R. (2022) Unlocking the Promise of mRNA Therapeutics. Nature Biotechnology, 40, 1586-1600. [Google Scholar] [CrossRef] [PubMed]
[6] Tombácz, I., Laczkó, D., Shahnawaz, H., Muramatsu, H., Natesan, A., Yadegari, A., et al. (2021) Highly Efficient CD4+ T Cell Targeting and Genetic Recombination Using Engineered CD4+ Cell-Homing mRNA-LNPs. Molecular Therapy, 29, 3293-3304. [Google Scholar] [CrossRef] [PubMed]
[7] Zarghampoor, F., Azarpira, N., Khatami, S.R., Behzad-Behbahani, A. and Foroughmand, A.M. (2019) Improved Translation Efficiency of Therapeutic mRNA. Gene, 707, 231-238. [Google Scholar] [CrossRef] [PubMed]
[8] Ziemniak, M., Strenkowska, M., Kowalska, J. and Jemielity, J. (2013) Potential Therapeutic Applications of RNA Cap Analogs. Future Medicinal Chemistry, 5, 1141-1172. [Google Scholar] [CrossRef] [PubMed]
[9] Orlandini von Niessen, A.G., Poleganov, M.A., Rechner, C., Plaschke, A., Kranz, L.M., Fesser, S., et al. (2019) Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3’ Utrs Identified by Cellular Library Screening. Molecular Therapy, 27, 824-836. [Google Scholar] [CrossRef] [PubMed]
[10] Roy, B. and Jacobson, A. (2013) The Intimate Relationships of mRNA Decay and Translation. Trends in Genetics, 29, 691-699. [Google Scholar] [CrossRef] [PubMed]
[11] Alexaki, A., Hettiarachchi, G.K., Athey, J.C., Katneni, U.K., Simhadri, V., Hamasaki-Katagiri, N., et al. (2019) Effects of Codon Optimization on Coagulation Factor IX Translation and Structure: Implications for Protein and Gene Therapies. Scientific Reports, 9, Article No. 15449. [Google Scholar] [CrossRef] [PubMed]
[12] Jiang, L., Berraondo, P., Jericó, D., Guey, L.T., Sampedro, A., Frassetto, A., et al. (2018) Systemic Messenger RNA as an Etiological Treatment for Acute Intermittent Porphyria. Nature Medicine, 24, 1899-1909. [Google Scholar] [CrossRef] [PubMed]
[13] Cao, J., An, D., Galduroz, M., Zhuo, J., Liang, S., Eybye, M., et al. (2019) MRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency. Molecular Therapy, 27, 1242-1251. [Google Scholar] [CrossRef] [PubMed]
[14] Sahin, U., Karikó, K. and Türeci, Ö. (2014) MRNA-Based Therapeutics—Developing a New Class of Drugs. Nature Reviews Drug Discovery, 13, 759-780. [Google Scholar] [CrossRef] [PubMed]
[15] Conry, R.M., Lobuglio, A.F., Wright, M., et al. (1995) Characterization of a Messenger RNA Polynucleotide Vaccine Vector. Cancer Research, 55, 1397-1400.
[16] Liu, M.A. (2019) A Comparison of Plasmid DNA and mRNA as Vaccine Technologies. Vaccines, 7, Article 37. [Google Scholar] [CrossRef] [PubMed]
[17] Hu, M., Li, X., You, Z., Cai, R. and Chen, C. (2024) Physiological Barriers and Strategies of Lipid‐Based Nanoparticles for Nucleic Acid Drug Delivery. Advanced Materials, 36, e2303266. [Google Scholar] [CrossRef] [PubMed]
[18] Eygeris, Y., Gupta, M., Kim, J. and Sahay, G. (2022) Chemistry of Lipid Nanoparticles for RNA Delivery. Accounts of Chemical Research, 55, 2-12. [Google Scholar] [CrossRef] [PubMed]
[19] Herrera, M., Kim, J., Eygeris, Y., Jozic, A. and Sahay, G. (2021) Illuminating Endosomal Escape of Polymorphic Lipid Nanoparticles That Boost mRNA Delivery. Biomaterials Science, 9, 4289-4300. [Google Scholar] [CrossRef] [PubMed]
[20] Kulkarni, J.A., Witzigmann, D., Leung, J., Tam, Y.Y.C. and Cullis, P.R. (2019) On the Role of Helper Lipids in Lipid Nanoparticle Formulations of Sirna. Nanoscale, 11, 21733-21739. [Google Scholar] [CrossRef] [PubMed]
[21] Hou, X., Zaks, T., Langer, R. and Dong, Y. (2021) Lipid Nanoparticles for mRNA Delivery. Nature Reviews Materials, 6, 1078-1094. [Google Scholar] [CrossRef] [PubMed]
[22] Hajj, K.A. and Whitehead, K.A. (2017) Tools for Translation: Non-Viral Materials for Therapeutic mRNA Delivery. Nature Reviews Materials, 2, Article No. 17056. [Google Scholar] [CrossRef] 
[23] Kowalski, P.S., Rudra, A., Miao, L. and Anderson, D.G. (2019) Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery. Molecular Therapy, 27, 710-728. [Google Scholar] [CrossRef] [PubMed]
[24] Pardi, N., Tuyishime, S., Muramatsu, H., Kariko, K., Mui, B.L., Tam, Y.K., et al. (2015) Expression Kinetics of Nucleoside-Modified mRNA Delivered in Lipid Nanoparticles to Mice by Various Routes. Journal of Controlled Release, 217, 345-351. [Google Scholar] [CrossRef] [PubMed]
[25] Wesselhoeft, R.A., Kowalski, P.S. and Anderson, D.G. (2018) Engineering Circular RNA for Potent and Stable Translation in Eukaryotic Cells. Nature Communications, 9, Article No. 2629. [Google Scholar] [CrossRef] [PubMed]
[26] Blau, N., van Spronsen, F.J. and Levy, H.L. (2010) Phenylketonuria. The Lancet, 376, 1417-1427. [Google Scholar] [CrossRef] [PubMed]
[27] 何卫兰, 唐芳, 鄢力, 等. 成都市20年新生儿苯丙酮尿症分析[J]. 江苏医药, 2016, 42(3): 310-311, 前插1.
[28] Chen, A., Pan, Y. and Chen, J. (2023) Clinical, Genetic, and Experimental Research of Hyperphenylalaninemia. Frontiers in Genetics, 13, Article 1051153. [Google Scholar] [CrossRef] [PubMed]
[29] Arnold, G.L., Vladutiu, C.J., Orlowski, C.C., Blakely, E.M. and DeLuca, J. (2004) Prevalence of Stimulant Use for Attentional Dysfunction in Children with Phenylketonuria. Journal of Inherited Metabolic Disease, 27, 137-143. [Google Scholar] [CrossRef] [PubMed]
[30] Pinto, A., Ilgaz, F., Evans, S., van Dam, E., Rocha, J.C., Karabulut, E., et al. (2023) Phenylalanine Tolerance over Time in Phenylketonuria: A Systematic Review and Meta-Analysis. Nutrients, 15, Article 3506. [Google Scholar] [CrossRef] [PubMed]
[31] Cunningham, A., Rohr, F., Splett, P., Mofidi, S., Bausell, H., Stembridge, A., et al. (2023) Nutrition Management of PKU with Pegvaliase Therapy: Update of the Web-Based PKU Nutrition Management Guideline Recommendations. Orphanet Journal of Rare Diseases, 18, Article No. 155. [Google Scholar] [CrossRef] [PubMed]
[32] Eshraghi, P., Noroozi Asl, S., Bagheri, S. and Chalak, V. (2019) Response to Sapropterin Hydrochloride (Kuvan®) in Children with Phenylketonuria (PKU): A Clinical Trial. Journal of Pediatric Endocrinology and Metabolism, 32, 885-888. [Google Scholar] [CrossRef] [PubMed]
[33] Cacicedo, M.L., Weinl-Tenbruck, C., Frank, D., Limeres, M.J., Wirsching, S., Hilbert, K., et al. (2022) Phenylalanine Hydroxylase mRNA Rescues the Phenylketonuria Phenotype in Mice. Frontiers in Bioengineering and Biotechnology, 10, Article 993298. [Google Scholar] [CrossRef] [PubMed]
[34] Diaz-Trelles, R., Lee, S., Kuakini, K., Park, J., Dukanovic, A., Gonzalez, J.A., et al. (2022) Lipid Nanoparticle Delivers Phenylalanine Ammonia Lyase mRNA to the Liver Leading to Catabolism and Clearance of Phenylalanine in a Phenylketonuria Mouse Model. Molecular Genetics and Metabolism Reports, 32, Article 100882. [Google Scholar] [CrossRef] [PubMed]
[35] Baek, R., Coughlan, K., Jiang, L., Liang, M., Ci, L., Singh, H., et al. (2024) Characterizing the Mechanism of Action for mRNA Therapeutics for the Treatment of Propionic Acidemia, Methylmalonic Acidemia, and Phenylketonuria. Nature Communications, 15, Article No. 3804. [Google Scholar] [CrossRef] [PubMed]
[36] 韩连书, 杨艳玲, 杨茹莱, 等. 丙酸血症筛查及诊治专家共识[J]. 中国实用儿科杂志, 2024, 39(4): 241-248.
[37] Chace, D.H., DiPerna, J.C., Kalas, T.A., Johnson, R.W. and Naylor, E.W. (2001) Rapid Diagnosis of Methylmalonic and Propionic Acidemias. Clinical Chemistry, 47, 2040-2044. [Google Scholar] [CrossRef] 
[38] Al-Hamed, M.H., Imtiaz, F., Al-Hassnan, Z., Al-Owain, M., Al-Zaidan, H., Alamoudi, M.S., et al. (2019) Spectrum of Mutations Underlying Propionic Acidemia and Further Insight into a Genotype-Phenotype Correlation for the Common Mutation in Saudi Arabia. Molecular Genetics and Metabolism Reports, 18, 22-29. [Google Scholar] [CrossRef] [PubMed]
[39] Manoli, I. and Venditti, C.P. (2016) Disorders of Branched Chain Amino Acid Metabolism. Translational Science of Rare Diseases, 1, 91-110. [Google Scholar] [CrossRef] [PubMed]
[40] Romano, S., Valayannopoulos, V., Touati, G., Jais, J., Rabier, D., de Keyzer, Y., et al. (2010) Cardiomyopathies in Propionic Aciduria Are Reversible after Liver Transplantation. The Journal of Pediatrics, 156, 128-134. [Google Scholar] [CrossRef] [PubMed]
[41] Hörster, F., Baumgartner, M.R., Viardot, C., Suormala, T., Burgard, P., Fowler, B., et al. (2007) Long-Term Outcome in Methylmalonic Acidurias Is Influenced by the Underlying Defect (mut0, mut−, cblA, cblB). Pediatric Research, 62, 225-230. [Google Scholar] [CrossRef] [PubMed]
[42] Sutton, V.R., Chapman, K.A., Gropman, A.L., MacLeod, E., Stagni, K., Summar, M.L., et al. (2012) Chronic Management and Health Supervision of Individuals with Propionic Acidemia. Molecular Genetics and Metabolism, 105, 26-33. [Google Scholar] [CrossRef] [PubMed]
[43] Chu, T., Chien, Y., Lin, H., Liao, H., Ho, H., Lai, C., et al. (2019) Methylmalonic Acidemia/Propionic Acidemia—The Biochemical Presentation and Comparing the Outcome between Liver Transplantation versus Non-Liver Transplantation Groups. Orphanet Journal of Rare Diseases, 14, Article No. 73. [Google Scholar] [CrossRef] [PubMed]
[44] Kasahara, M., Horikawa, R., Tagawa, M., Uemoto, S., Yokoyama, S., Shibata, Y., et al. (2006) Current Role of Liver Transplantation for Methylmalonic Acidemia: A Review of the Literature. Pediatric Transplantation, 10, 943-947. [Google Scholar] [CrossRef] [PubMed]
[45] Jiang, L., Park, J., Yin, L., Laureano, R., Jacquinet, E., Yang, J., et al. (2020) Dual mRNA Therapy Restores Metabolic Function in Long-Term Studies in Mice with Propionic Acidemia. Nature Communications, 11, Article No. 5339. [Google Scholar] [CrossRef] [PubMed]
[46] Attarwala, H., Lumley, M., Liang, M., Ivaturi, V. and Senn, J. (2023) Translational Pharmacokinetic/Pharmacodynamic Model for mRNA-3927, an Investigational Therapeutic for the Treatment of Propionic Acidemia. Nucleic Acid Therapeutics, 33, 141-147. [Google Scholar] [CrossRef] [PubMed]
[47] An, D., Schneller, J.L., Frassetto, A., Liang, S., Zhu, X., Park, J., et al. (2017) Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia. Cell Reports, 21, 3548-3558. [Google Scholar] [CrossRef] [PubMed]
[48] Critelli, K., McKiernan, P., Vockley, J., Mazariegos, G., Squires, R.H., Soltys, K., et al. (2018) Liver Transplantation for Propionic Acidemia and Methylmalonic Acidemia: Perioperative Management and Clinical Outcomes. Liver Transplantation, 24, 1260-1270. [Google Scholar] [CrossRef] [PubMed]
[49] Chen, P.W., Hwu, W.L., Ho, M.C., Lee, N.C., Chien, Y.H., Ni, Y.H., et al. (2010) Stabilization of Blood Methylmalonic Acid Level in Methylmalonic Acidemia after Liver Transplantation. Pediatric Transplantation, 14, 337-341. [Google Scholar] [CrossRef] [PubMed]
[50] An, D., Frassetto, A., Jacquinet, E., Eybye, M., Milano, J., DeAntonis, C., et al. (2019) Long-Term Efficacy and Safety of mRNA Therapy in Two Murine Models of Methylmalonic Acidemia. EBioMedicine, 45, 519-528. [Google Scholar] [CrossRef] [PubMed]
[51] Batshaw, M.L., Tuchman, M., Summar, M. and Seminara, J. (2014) A Longitudinal Study of Urea Cycle Disorders. Molecular Genetics and Metabolism, 113, 127-130. [Google Scholar] [CrossRef] [PubMed]
[52] Dionisi-Vici, C., Rizzo, C., Burlina, A.B., Caruso, U., Sabetta, G., Uziel, G., et al. (2002) Inborn Errors of Metabolism in the Italian Pediatric Population: A National Retrospective Survey. The Journal of Pediatrics, 140, 321-329. [Google Scholar] [CrossRef] [PubMed]
[53] Keskinen, P., Siitonen, A. and Salo, M. (2008) Hereditary Urea Cycle Diseases in Finland. Acta Paediatrica, 97, 1412-1419. [Google Scholar] [CrossRef] [PubMed]
[54] Seker Yilmaz, B., Baruteau, J., Arslan, N., Aydin, H.I., Barth, M., Bozaci, A.E., et al. (2022) Three-Country Snapshot of Ornithine Transcarbamylase Deficiency. Life, 12, Article 1721. [Google Scholar] [CrossRef] [PubMed]
[55] Brassier, A., Gobin, S., Arnoux, J.B., Valayannopoulos, V., Habarou, F., Kossorotoff, M., et al. (2015) Long-Term Outcomes in Ornithine Transcarbamylase Deficiency: A Series of 90 Patients. Orphanet Journal of Rare Diseases, 10, Article No. 58. [Google Scholar] [CrossRef] [PubMed]
[56] Lu, D., Han, F., Qiu, W., Zhang, H., Ye, J., Liang, L., et al. (2020) Clinical and Molecular Characteristics of 69 Chinese Patients with Ornithine Transcarbamylase Deficiency. Orphanet Journal of Rare Diseases, 15, Article No. 340. [Google Scholar] [CrossRef] [PubMed]
[57] Foschi, F.G. (2015) Urea Cycle Disorders: A Case Report of a Successful Treatment with Liver Transplant and a Literature Review. World Journal of Gastroenterology, 21, 4063-4068. [Google Scholar] [CrossRef] [PubMed]
[58] Prieve, M.G., Harvie, P., Monahan, S.D., Roy, D., Li, A.G., Blevins, T.L., et al. (2018) Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency. Molecular Therapy, 26, 801-813. [Google Scholar] [CrossRef] [PubMed]
[59] Yu, H., Brewer, E., Shields, M., Crowder, M., Sacchetti, C., Soontornniyomkij, B., et al. (2022) Restoring Ornithine Transcarbamylase (OTC) Activity in an OTC‐Deficient Mouse Model Using LUNAR‐OTC mRNA. Clinical and Translational Discovery, 2, e33. [Google Scholar] [CrossRef] 
[60] Yamazaki, K., Kubara, K., Ishii, S., Kondo, K., Suzuki, Y., Miyazaki, T., et al. (2023) Lipid Nanoparticle-Targeted mRNA Formulation as a Treatment for Ornithine-Transcarbamylase Deficiency Model Mice. Molecular Therapy—Nucleic Acids, 33, 210-226. [Google Scholar] [CrossRef] [PubMed]

为你推荐