儿童罕见病药物治疗新进展

doi:10.7499/j.issn.1008-8830.2302048

摘要
图/表
参考文献(71)
相关文章 (15)
点击分布统计
下载分布统计

全文: PDF (785 KB) [HTML]
输出: BibTeX | EndNote (RIS) 背景资料

摘要罕见病有7 000余种，全球罕见病患者总数约4.75亿，其中儿童占2/3。因每种罕见病的患病人群基数小，制药企业研发资金有限，仍有几千种罕见病还没有获得批准的治疗药物。目前，95%的罕见病患者尚无药可治，因此能够治疗罕见病的药物被称为孤儿药。为引导制药公司加大孤儿药开发力度，多国制定了罕见病药物法案，推进简化孤儿药专利申请程序，积极为孤儿药研发提供科学建议和指导。儿童是罕见病的高发群体，该文将围绕儿童罕见病药物治疗新进展进行综述。

	服务

	把本文推荐给朋友
	加入我的书架
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	李佳琦
	王慧君

关键词 ：罕见病, 孤儿药生产, 酶替代疗法, 小分子药物, 基因治疗, 儿童

Abstract：There are more than 7 000 rare diseases and approximately 475 million individuals with rare diseases globally, with children accounting for two-thirds of this population. Due to a relatively small patient population and limited financial resources allocated for drug research and development in pharmaceutical enterprises, there are still no drugs approved for the treatment of several thousands of these rare diseases. At present, there are no drugs for 95% of the patients with rare diseases, and consequently, the therapeutic drugs for rare diseases have been designated as orphan drugs. In order to guide pharmaceutical enterprises to strengthen the research and development of orphan drugs, various nations have enacted the acts for rare disease drugs, promoted and simplified the patent application process for orphan drugs, and provided scientific recommendations and guidance for the research and development of orphan drugs. Since there is a relatively high incidence rate of rare diseases in children, this article reviews the latest research on pharmacotherapy for children with rare diseases.

Key words： Rare disease Orphan drug production Enzyme replacement therapy Small-molecule drug Gene therapy Child

收稿日期: 2023-02-08

通讯作者: 周文浩，男，教授。Email：zhouwenhao@fudan.edu.cn。 E-mail: zhouwenhao@fudan.edu.cn

作者简介: 李佳琦，女，硕士研究生；

引用本文:

李佳琦,王慧君. 儿童罕见病药物治疗新进展[J]. 中国当代儿科杂志, 2023, 25(7): 759-766.

LI Jia-Qi,WANG Hui-Jun. Research advances in pharmacotherapy for rare diseases in children[J]. CJCP, 2023, 25(7): 759-766.

链接本文:

http://www.zgddek.com/CN/10.7499/j.issn.1008-8830.2302048 或 http://www.zgddek.com/CN/Y2023/V25/I7/759

	1 97th United States Congress. Public law 97-414 an act to amend the Federal Food, Drug, and Cosmetic Act to facilitate the development of drugs for rare diseases and conditions, and for other purposes[Z]. Washington: Senate and House of Representatives of the United States of America in Congress assembled, 1983.
	2 尹薇. 中国罕见病定义研究报告发布: 患病人数小于14万为罕见病[EB/OL]. (2021-09-12)[2023-03-15]. https://baijiahao.baidu.com/s?id=1710682019865110353&wfr=spider&for=pc.
	Rubin R. New funding for research into rare diseases treatments[J]. JAMA, 2022, 328(19): 1898-1899. PMID: 36378219. DOI: 10.1001/jama.2022.18479.
	4 陈晨, 韩晓红. 中国罕见病药物临床试验10年现状分析:基于《第一批罕见病目录》[J]. 协和医学杂志, 2022, 13(6): 1028-1035. DOI: 10.12290/xhyxzz.2022-0010.
	Lachmann RH. Treating lysosomal storage disorders: what have we learnt?[J]. J Inherit Metab Dis, 2020, 43(1): 125-132. PMID: 31140601. DOI: 10.1002/jimd.12131.
	Kleppin S. Enzyme replacement therapy for lysosomal storage diseases[J]. J Infus Nurs, 2020, 43(5): 243-245. PMID: 32881810. DOI: 10.1097/NAN.0000000000000390.
	Parini R, Deodato F. Intravenous enzyme replacement therapy in mucopolysaccharidoses: clinical effectiveness and limitations[J]. Int J Mol Sci, 2020, 21(8): 2975. PMID: 32340185. PMCID: PMC7215308. DOI: 10.3390/ijms21082975.
	Jameson E, Jones S, Remmington T. Enzyme replacement therapy with laronidase (Aldurazyme?) for treating mucopolysaccharidosis type I[J]. Cochrane Database Syst Rev, 2019, 6(6): CD009354. PMID: 31211405. PMCID: PMC6581069. DOI: 10.1002/14651858.CD009354.pub5.
	Muenzer J, Vijayaraghavan S, Stein M, et al. Long-term open-label phase I/II extension study of intrathecal idursulfase-IT in the treatment of neuronopathic mucopolysaccharidosis II[J]. Genet Med, 2022, 24(7): 1437-1448. PMID: 35588317. DOI: 10.1016/j.gim.2022.04.002.
	Wijburg FA, Heap F, Rust S, et al. Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A[J]. Mol Genet Metab, 2021, 134(4): 317-322. PMID: 34600820. DOI: 10.1016/j.ymgme.2021.09.003.
	Lee CL, Chuang CK, Chiu HC, et al. Clinical utility of elosulfase alfa in the treatment of Morquio A syndrome[J]. Drug Des Devel Ther, 2022, 16: 143-154. PMID: 35046639. PMCID: PMC8759989. DOI: 10.2147/DDDT.S219433.
	Dubot P, Sabourdy F, Plat G, et al. First report of a patient with MPS type VII, due to novel mutations in GUSB, who underwent enzyme replacement and then hematopoietic stem cell transplantation[J]. Int J Mol Sci, 2019, 20(21): 5345. PMID: 31661765. PMCID: PMC6861985. DOI: 10.3390/ijms20215345.
	Nakamura K, Kawashima S, Tozawa H, et al. Pharmacokinetics and pharmacodynamics of JR-051, a biosimilar of agalsidase beta, in healthy adults and patients with Fabry disease: phase I and II/III clinical studies[J]. Mol Genet Metab, 2020, 130(3): 215-224. PMID: 32389574. DOI: 10.1016/j.ymgme.2020.04.003.
	Diaz GA, Jones SA, Scarpa M, et al. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency[J]. Genet Med, 2021, 23(8): 1543-1550. PMID: 33875845. PMCID: PMC8354848. DOI: 10.1038/s41436-021-01156-3.
	Sagara R, Ishigaki M, Otsuka M, et al. Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan[J]. Orphanet J Rare Dis, 2021, 16(1): 502. PMID: 34863216. PMCID: PMC8642863. DOI: 10.1186/s13023-021-02119-2.
	Okuyama T, Eto Y, Sakai N, et al. A phase 2/3 trial of pabinafusp alfa, IDS fused with anti-human transferrin receptor antibody, targeting neurodegeneration in MPS-II[J]. Mol Ther, 2021, 29(2): 671-679. PMID: 33038326. PMCID: PMC7854283. DOI: 10.1016/j.ymthe.2020.09.039.
	Diaz-Manera J, Kishnani PS, Kushlaf H, et al. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial[J]. Lancet Neurol, 2021, 20(12): 1012-1026. PMID: 34800399. DOI: 10.1016/S1474-4422(21)00241-6.
	Schmidt D, Thompson C. Case studies in rare disease small molecule discovery and development[J]. Bioorg Med Chem Lett, 2020, 30(21): 127462. PMID: 32791196. DOI: 10.1016/j.bmcl.2020.127462.
	Tambuyzer E, Vandendriessche B, Austin CP, et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead[J]. Nat Rev Drug Discov, 2020, 19(2): 93-111. PMID: 31836861. DOI: 10.1038/s41573-019-0049-9.
	Scotet V, Gutierrez H, Farrell PM. Newborn screening for CF across the globe—where is it worthwhile?[J]. Int J Neonatal Screen, 2020, 6(1): 18. PMID: 33073015. PMCID: PMC7422974. DOI: 10.3390/ijns6010018.
	Mall MA, Mayer-Hamblett N, Rowe SM. Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications[J]. Am J Respir Crit Care Med, 2020, 201(10): 1193-1208. PMID: 31860331. PMCID: PMC7233349. DOI: 10.1164/rccm.201910-1943SO.
	Bobadilla JL, Macek M, Fine JP, et al. Cystic fibrosis: a worldwide analysis of CFTR mutations—correlation with incidence data and application to screening[J]. Hum Mutat, 2002, 19(6): 575-606. PMID: 12007216. DOI: 10.1002/humu.10041.
	Yu H, Burton B, Huang CJ, et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations[J]. J Cyst Fibros, 2012, 11(3): 237-245. PMID: 22293084. DOI: 10.1016/j.jcf.2011.12.005.
	Liu J, Berg AP, Wang Y, et al. A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR[J]. Br J Pharmacol, 2022, 179(7): 1319-1337. PMID: 34644413. PMCID: PMC9304199. DOI: 10.1111/bph.15709.
	Wang J, Yu Q, Ma X, et al. Hutchinson-Gilford progeria syndrome complicated with stroke: a report of 2 cases and literature review[J]. Front Pediatr, 2022, 10: 1056225. PMID: 36523395. PMCID: PMC9745312. DOI: 10.3389/fped.2022.1056225.
	Koblan LW, Erdos MR, Wilson C, et al. In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice[J]. Nature, 2021, 589(7843): 608-614. PMID: 33408413. PMCID: PMC7872200. DOI: 10.1038/s41586-020-03086-7.
	Chang W, Wang Y, Luxton GWG, et al. Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging[J]. Proc Natl Acad Sci U S A, 2019, 116(9): 3578-3583. PMID: 30808750. PMCID: PMC6397528. DOI: 10.1073/pnas.1809683116.
	Macicior J, Marcos-Ramiro B, Ortega-Gutiérrez S. Small-molecule therapeutic perspectives for the treatment of progeria[J]. Int J Mol Sci, 2021, 22(13): 7190. PMID: 34281245. PMCID: PMC8267806. DOI: 10.3390/ijms22137190.
	Dhillon S. Lonafarnib: first approval[J]. Drugs, 2021, 81(2): 283-289. PMID: 33590450. PMCID: PMC7985116. DOI: 10.1007/s40265-020-01464-z.
	Marcos-Ramiro B, Gil-Ordó?ez A, Marín-Ramos NI, et al. Isoprenylcysteine carboxylmethyltransferase-based therapy for Hutchinson-Gilford progeria syndrome[J]. ACS Cent Sci, 2021, 7(8): 1300-1310. PMID: 34471675. PMCID: PMC8393201. DOI: 10.1021/acscentsci.0c01698.
	Lee SJ, Jung YS, Yoon MH, et al. Interruption of progerin-lamin A/C binding ameliorates Hutchinson-Gilford progeria syndrome phenotype[J]. J Clin Invest, 2016, 126(10): 3879-3893. PMID: 27617860. PMCID: PMC5096810. DOI: 10.1172/JCI84164.
	Larrieu D, Britton S, Demir M, et al. Chemical inhibition of NAT10 corrects defects of laminopathic cells[J]. Science, 2014, 344(6183): 527-532. PMID: 24786082. PMCID: PMC4246063. DOI: 10.1126/science.1252651.
	Balmus G, Larrieu D, Barros AC, et al. Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome[J]. Nat Commun, 2018, 9(1): 1700. PMID: 29703891. PMCID: PMC5923383. DOI: 10.1038/s41467-018-03770-3.
	Zeng R, Glaubitz S, Schmidt J. Antibody therapies in autoimmune inflammatory myopathies: promising treatment options[J]. Neurotherapeutics, 2022, 19(3): 911-921. PMID: 35394612. PMCID: PMC9294121. DOI: 10.1007/s13311-022-01220-z.
	Ossart J, Moreau A, Autrusseau E, et al. Breakdown of immune tolerance in AIRE-deficient rats induces a severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-like autoimmune disease[J]. J Immunol, 2018, 201(3): 874-887. PMID: 29959280. DOI: 10.4049/jimmunol.1701318.
	Chascsa DM, Ferré EMN, Hadjiyannis Y, et al. APECED-associated hepatitis: clinical, biochemical, histological and treatment data from a large, predominantly American cohort[J]. Hepatology, 2021, 73(3): 1088-1104. PMID: 32557834. PMCID: PMC9169991. DOI: 10.1002/hep.31421.
	Besnard M, Padonou F, Provin N, et al. AIRE deficiency, from preclinical models to human APECED disease[J]. Dis Model Mech, 2021, 14(2): dmm046359. PMID: 33729987. PMCID: PMC7875492. DOI: 10.1242/dmm.046359.
	Besnard M, Sérazin C, Ossart J, et al. Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome[J]. J Clin Invest, 2022, 132(7): e156507. PMID: 35167497. PMCID: PMC8970675. DOI: 10.1172/JCI156507.
	de Souza FHC, Miossi R, de Moraes JCB, et al. Favorable rituximab response in patients with refractory idiopathic inflammatory myopathies[J]. Adv Rheumatol, 2018, 58(1): 31. PMID: 30657080. DOI: 10.1186/s42358-018-0030-z.
	Dunbar CE, High KA, Joung JK, et al. Gene therapy comes of age[J]. Science, 2018, 359(6372): eaan4672. PMID: 29326244. DOI: 10.1126/science.aan4672.
	Zhang XE, Liu C, Dai J, et al. Enabling technology and core theory of synthetic biology[J]. Sci China Life Sci, 2023: 1-44. PMID: 36753021. PMCID: PMC9907219. DOI: 10.1007/s11427-022-2214-2. Epub ahead of print.
	42 桂怡婷, 李强, 桂永浩. 罕见病的基因治疗应用与展望[J]. 临床儿科杂志, 2020, 38(10): 794-798. DOI: 10.3969/j.issn.1000-3606.2020.10.018.
	Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current clinical applications of in vivo gene therapy with AAVs[J]. Mol Ther, 2021, 29(2): 464-488. PMID: 33309881. PMCID: PMC7854298. DOI: 10.1016/j.ymthe.2020.12.007.
	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. PMID: 33558455. PMCID: PMC7868676. DOI: 10.1038/s41392-021-00487-6.
	Huang CH, Yang CM, Yang CH, et al. Leber's congenital amaurosis: current concepts of genotype-phenotype correlations[J]. Genes (Basel), 2021, 12(8): 1261. PMID: 34440435. PMCID: PMC8392113. DOI: 10.3390/genes12081261.
	Padhy SK, Takkar B, Narayanan R, et al. Voretigene neparvovec and gene therapy for Leber's congenital amaurosis: review of evidence to date[J]. Appl Clin Genet, 2020, 13: 179-208. PMID: 33268999. PMCID: PMC7701157. DOI: 10.2147/TACG.S230720.
	Gange WS, Sisk RA, Besirli CG, et al. Perifoveal chorioretinal atrophy after subretinal voretigene neparvovec-rzyl for RPE65-mediated Leber congenital amaurosis[J]. Ophthalmol Retina, 2022, 6(1): 58-64. PMID: 33838313. PMCID: PMC8497635. DOI: 10.1016/j.oret.2021.03.016.
	Tjondrokoesoemo A, Schips TG, Sargent MA, et al. Cathepsin S contributes to the pathogenesis of muscular dystrophy in mice[J]. J Biol Chem, 2016, 291(19): 9920-9928. PMID: 26966179. PMCID: PMC4858995. DOI: 10.1074/jbc.M116.719054.
	Asher DR, Thapa K, Dharia SD, et al. Clinical development on the frontier: gene therapy for Duchenne muscular dystrophy[J]. Expert Opin Biol Ther, 2020, 20(3): 263-274. PMID: 32031420. DOI: 10.1080/14712598.2020.1725469.
	Abreu NJ, Waldrop MA. Overview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy[J]. Pediatr Pulmonol, 2021, 56(4): 710-720. PMID: 32886442. DOI: 10.1002/ppul.25055.
	Song Y, Morales L, Malik AS, et al. Non-immunogenic utrophin gene therapy for the treatment of muscular dystrophy animal models[J]. Nat Med, 2019, 25(10): 1505-1511. PMID: 31591596. PMCID: PMC7274039. DOI: 10.1038/s41591-019-0594-0.
	52 Malik MA, Masab M. Wiskott-Aldrich Syndrome[M]//StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.
	Magnani A, Semeraro M, Adam F, et al. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome[J]. Nat Med, 2022, 28(1): 71-80. PMID: 35075289. PMCID: PMC8799465. DOI: 10.1038/s41591-021-01641-x.
	Rai R, Romito M, Rivers E, et al. Targeted gene correction of human hematopoietic stem cells for the treatment of Wiskott-Aldrich syndrome[J]. Nat Commun, 2020, 11(1): 4034. PMID: 32788576. PMCID: PMC7423939. DOI: 10.1038/s41467-020-17626-2.
	Ciftciler R, Goker H, Buyukas?k Y, et al. The experience of allogeneic hematopoietic stem cell transplantation in a patient with X-linked adrenoleukodystrophy[J]. Transfus Apher Sci, 2020, 59(1): 102583. PMID: 31350055. DOI: 10.1016/j.transci.2019.06.019.
	Zhu J, Eichler F, Biffi A, et al. The changing face of adrenoleukodystrophy[J]. Endocr Rev, 2020, 41(4): 577-593. PMID: 32364223. PMCID: PMC7286618. DOI: 10.1210/endrev/bnaa013.
	Klim JR, Vance C, Scotter EL. Antisense oligonucleotide therapies for amyotrophic lateral sclerosis: existing and emerging targets[J]. Int J Biochem Cell Biol, 2019, 110: 149-153. PMID: 30904737. DOI: 10.1016/j.biocel.2019.03.009.
	Aoki Y, Wood MJA. Emerging oligonucleotide therapeutics for rare neuromuscular diseases[J]. J Neuromuscul Dis, 2021, 8(6): 869-884. PMID: 34092651. PMCID: PMC8673547. DOI: 10.3233/JND-200560.
	Miller TM, Pestronk A, David W, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study[J]. Lancet Neurol, 2013, 12(5): 435-442. PMID: 23541756. PMCID: PMC3712285. DOI: 10.1016/S1474-4422(13)70061-9.
	Alfano LN, Charleston JS, Connolly AM, et al. Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy[J]. Medicine (Baltimore), 2019, 98(26): e15858. PMID: 31261494. PMCID: PMC6617421. DOI: 10.1097/MD.0000000000015858.
	Aartsma-Rus A, Arechavala-Gomeza V. Why dystrophin quantification is key in the eteplirsen saga[J]. Nat Rev Neurol, 2018, 14(8): 454-456. PMID: 29967362. DOI: 10.1038/s41582-018-0033-8.
	Frank DE, Schnell FJ, Akana C, et al. Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy[J]. Neurology, 2020, 94(21): e2270-e2282. PMID: 32139505. PMCID: PMC7357297. DOI: 10.1212/WNL.0000000000009233.
	McShane A, Mole SE. Sex bias and omission exists in Batten disease research: systematic review of the use of animal disease models[J]. Biochim Biophys Acta Mol Basis Dis, 2022, 1868(11): 166489. PMID: 35840041. DOI: 10.1016/j.bbadis.2022.166489.
	Kim J, Hu C, Moufawad El Achkar C, et al. Patient-customized oligonucleotide therapy for a rare genetic disease[J]. N Engl J Med, 2019, 381(17): 1644-1652. PMID: 31597037. PMCID: PMC6961983. DOI: 10.1056/NEJMoa1813279.
	Rubio T, Viana R, Moreno-Estellés M, et al. TNF and IL6/Jak2 signaling pathways are the main contributors of the glia-derived neuroinflammation present in Lafora disease, a fatal form of progressive myoclonus epilepsy[J]. Neurobiol Dis, 2023, 176: 105964. PMID: 36526090. DOI: 10.1016/j.nbd.2022.105964.
	Mollá B, Heredia M, Sanz P. Modulators of neuroinflammation have a beneficial effect in a Lafora disease mouse model[J]. Mol Neurobiol, 2021, 58(6): 2508-2522. PMID: 33447969. PMCID: PMC8167455. DOI: 10.1007/s12035-021-02285-1.
	Cuesta AM, Gallardo-Vara E, Casado-Vela J, et al. The role of propranolol as a repurposed drug in rare vascular diseases[J]. Int J Mol Sci, 2022, 23(8): 4217. PMID: 35457036. PMCID: PMC9025921. DOI: 10.3390/ijms23084217.
	Dimiene I, Bieksiene K, Zaveckiene J, et al. Effective initial treatment of diffuse pulmonary lymphangiomatosis with sirolimus and propranolol: a case report[J]. Medicina (Kaunas), 2021, 57(12): 1308. PMID: 34946253; PMCID:PMC8706407. DOI: 10.3390/medicina57121308.
	Davison AS, Norman B, Milan AM, et al. Assessment of the effect of once daily nitisinone therapy on 24-h urinary metadrenalines and 5-hydroxyindole acetic acid excretion in patients with alkaptonuria after 4 weeks of treatment[J]. JIMD Rep, 2018, 41: 1-10. PMID: 29147990. PMCID: PMC6122050. DOI: 10.1007/8904_2017_72.
	Zatkova A, Ranganath L, Kadasi L. Alkaptonuria: current perspectives[J]. Appl Clin Genet, 2020, 13: 37-47. PMID: 32158253. PMCID: PMC6986890. DOI: 10.2147/TACG.S186773.
	Vilboux T, Kayser M, Introne W, et al. Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria[J]. Hum Mutat, 2009, 30(12): 1611-1619. PMID: 19862842. PMCID: PMC2830005. DOI: 10.1002/humu.21120.