Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia; Children's Hospital at Westmead Clinical School, University of Sydney, Sydney, NSW, Australia; Gene Therapy Research Unit, Children's Medical Research Institute, Sydney, NSW, Australia.
Monash Heart and Monash Children's Hospital, Monash Health, Melbourne, Vic, Australia; Monash Cardiovascular Research Centre, Victorian Heart Institute, Melbourne, Vic, Australia; Monash Genetics, Monash Health, Melbourne, Vic, Australia; Department of Genomic Medicine, The Royal Melbourne Hospital, Parkville, Vic, Australia; Department of Paediatrics, Monash University Clayton, Vic, Australia.
Heart Lung Circ. 2023 Jul;32(7):769-779. doi: 10.1016/j.hlc.2023.01.017. Epub 2023 Apr 1.
The clinical outcome for children and adolescents with homozygous familial hypercholesterolaemia (HoFH) can be devastating, and treatment options are limited in the presence of a null variant. In HoFH, atherosclerotic risk accumulates from birth. Gene therapy is an appealing treatment option as restoration of low-density lipoprotein receptor (LDLR) gene function could provide a cure for HoFH. A clinical trial using a recombinant adeno-associated vector (rAAV) to deliver LDLR DNA to adult patients with HoFH was recently completed; results have not yet been reported. However, this treatment strategy may face challenges when translating to the paediatric population. The paediatric liver undergoes substantial growth which is significant as rAAV vector DNA persists primarily as episomes (extra-chromosomal DNA) and are not replicated during cell division. Therefore, rAAV-based gene addition treatment administered in childhood would likely only have a transient effect. With over 2,000 unique variants in LDLR, a goal of genomic editing-based therapy development would be to treat most (if not all) mutations with a single set of reagents. For a robust, durable effect, LDLR must be repaired in the genome of hepatocytes, which could be achieved using genomic editing technology such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and a DNA repair strategy such as homology-independent targeted integration. This review discusses this issue in the context of the paediatric patient group with severe compound heterozygous or homozygous null variants which are associated with aggressive early-onset atherosclerosis and myocardial infarction, together with the important pre-clinical studies that use genomic editing strategies to treat HoFH in place of apheresis and liver transplantation.
儿童和青少年纯合家族性高胆固醇血症（HoFH）的临床结局可能是灾难性的，并且在存在无效变异体的情况下，治疗选择有限。在 HoFH 中，动脉粥样硬化风险从出生开始积累。基因治疗是一种有吸引力的治疗选择，因为恢复低密度脂蛋白受体（LDLR）基因功能可以为 HoFH 提供治愈方法。最近完成了一项使用重组腺相关病毒（rAAV）将 LDLR DNA 递送至 HoFH 成年患者的临床试验；结果尚未报告。然而，当将这种治疗策略转化为儿科人群时，可能会面临挑战。儿科肝脏会经历大量的生长，这很重要，因为 rAAV 载体 DNA 主要作为附加体（染色体外 DNA）存在，并且在细胞分裂过程中不会复制。因此，在儿童期给予基于 rAAV 的基因添加治疗可能只会产生短暂的效果。由于 LDLR 有超过 2000 个独特的变异体，基于基因组编辑的治疗开发的目标是用一组试剂治疗大多数（如果不是全部）突变。为了获得稳健、持久的效果，LDLR 必须在肝细胞的基因组中得到修复，这可以通过使用基因组编辑技术（如成簇规律间隔短回文重复序列（CRISPR）/Cas9 和 DNA 修复策略（如非同源性靶向整合）来实现。本综述在儿科患者群体的背景下讨论了这一问题，这些患者患有严重的复合杂合子或纯合子无效变异体，与侵袭性早发动脉粥样硬化和心肌梗死有关，同时还讨论了使用基因组编辑策略替代血浆去除和肝移植治疗 HoFH 的重要临床前研究。
