Establishment of the Effectiveness of Early Versus Late Stem Cell Gene Therapy in Mucopolysaccharidosis II for Treating Central Versus Peripheral Disease.

IF 3.9 3区 医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Human gene therapy Pub Date : 2024-04-01 Epub Date: 2023-08-30 DOI:10.1089/hum.2023.002
Oriana Mandolfo, Aiyin Liao, Esha Singh, Claire O'leary, Rebecca J Holley, Brian W Bigger
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Abstract

Mucopolysaccharidosis type II (MPSII) is a rare pediatric X-linked lysosomal storage disease, caused by heterogeneous mutations in the iduronate-2-sulfatase (IDS) gene, which result in accumulation of heparan sulfate (HS) and dermatan sulfate within cells. This leads to severe skeletal abnormalities, hepatosplenomegaly, and cognitive deterioration. The progressive nature of the disease is a huge obstacle to achieve full neurological correction. Although current therapies can only treat somatic symptoms, a lentivirus-based hematopoietic stem cell gene therapy (HSCGT) approach has recently achieved improved central nervous system (CNS) neuropathology in the MPSII mouse model following transplant at 2 months of age. In this study, we evaluate neuropathology progression in 2-, 4- and 9-month-old MPSII mice, and using the same HSCGT strategy, we investigated somatic and neurological disease attenuation following treatment at 4 months of age. Our results showed gradual accumulation of HS between 2 and 4 months of age, but full manifestation of microgliosis/astrogliosis as early as 2 months. Late HSCGT fully reversed the somatic symptoms, thus achieving the same degree of peripheral correction as early therapy. However, late treatment resulted in slightly decreased efficacy in the CNS, with poorer brain enzymatic activity, together with reduced normalization of HS oversulfation. Overall, our findings confirm significant lysosomal burden and neuropathology in 2-month-old MPSII mice. Peripheral disease is readily reversible by LV.IDS-HSCGT regardless of age of transplant, suggesting a viable treatment for somatic disease. However, in the brain, higher IDS enzyme levels are achievable with early HSCGT treatment, and later transplant seems to be less effective, supporting the view that the earlier patients are diagnosed and treated, the better the therapy outcome.

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确定干细胞基因疗法在黏多醣症 II 中治疗中枢和外周疾病的早期和晚期疗效。
II型粘多糖病(MPSII)是一种罕见的小儿X连锁溶酶体贮积病,由iduronate-2-sulfatase(IDS)基因的异质性突变引起,导致硫酸肝素(HS)和硫酸真皮素在细胞内蓄积。这会导致严重的骨骼畸形、肝脾肿大和认知能力衰退。该病的进展性是实现全面神经矫正的巨大障碍。虽然目前的疗法只能治疗躯体症状,但基于慢病毒的造血干细胞基因治疗(HSCGT)方法最近在MPSII小鼠模型中实现了2月龄移植后中枢神经系统(CNS)神经病理学的改善。在本研究中,我们评估了2个月、4个月和9个月大的MPSII小鼠的神经病理学进展,并采用相同的HSCGT策略,研究了4个月大时治疗后体细胞和神经系统疾病的减轻情况。我们的研究结果表明,HS 在小鼠 2 个月至 4 个月大期间逐渐累积,但早在 2 个月大时就已完全表现出微神经胶质细胞病变/astrogliosis。晚期 HSCGT 可完全逆转躯体症状,从而达到与早期治疗相同的外周矫正程度。然而,晚期治疗导致中枢神经系统的疗效略有下降,脑部酶活性较差,HS 过度硫化的正常化程度也有所降低。总之,我们的研究结果证实,2 个月大的 MPSII 小鼠体内存在大量溶酶体负担和神经病理学。无论移植年龄多大,LV.IDS-HSCGT 都能轻易逆转外周疾病,这表明这是一种治疗躯体疾病的可行方法。然而,在大脑中,早期的 HSCGT 治疗可达到较高的 IDS 酶水平,而晚期移植的效果似乎较差,这支持了患者越早诊断和治疗,治疗效果越好的观点。
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来源期刊
Human gene therapy
Human gene therapy 医学-生物工程与应用微生物
CiteScore
6.50
自引率
4.80%
发文量
131
审稿时长
4-8 weeks
期刊介绍: Human Gene Therapy is the premier, multidisciplinary journal covering all aspects of gene therapy. The Journal publishes in-depth coverage of DNA, RNA, and cell therapies by delivering the latest breakthroughs in research and technologies. Human Gene Therapy provides a central forum for scientific and clinical information, including ethical, legal, regulatory, social, and commercial issues, which enables the advancement and progress of therapeutic procedures leading to improved patient outcomes, and ultimately, to curing diseases.
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