Abstract：
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.
摘要：
纯合子家族性高胆固醇血症（HoFH）的儿童和青少年的临床结果可能是毁灭性的，在存在无效变体的情况下，治疗选择是有限的。在HoFH,动脉粥样硬化的风险从出生积累。基因治疗是一种有吸引力的治疗选择，因为低密度脂蛋白受体（LDLR）基因功能的恢复可以治愈HoFH。最近完成了一项使用重组腺相关载体（rAAV）将LDLRDNA递送至成年HoFH患者的临床试验；结果尚未报道。然而,这种治疗策略在转化为儿科人群时可能面临挑战.儿科肝脏经历显著的生长,这是显著的,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期间不被复制。因此,在儿童期施用的基于rAAV的基因添加治疗可能仅具有短暂作用。LDLR中有超过2,000种独特的变体，基于基因组编辑的疗法开发的目标是用一组试剂治疗大多数(如果不是全部的话)突变.对于一个健壮的，持久的效果，LDLR必须在肝细胞的基因组中修复，这可以使用基因组编辑技术来实现，例如成簇的规则间隔的短回文重复序列（CRISPR）/Cas9和DNA修复策略，例如不依赖同源性的靶向整合。这篇综述在儿科患者组中讨论了这个问题，这些患者患有严重的复合杂合或纯合无效变异，这些变异与侵袭性早发性动脉粥样硬化和心肌梗塞有关。以及使用基因组编辑策略代替单采和肝移植治疗HoFH的重要临床前研究。
