Gene Therapy for Paediatric Homozygous Familial Hypercholesterolaemia

Lara E Graves; Ari Horton; Ian E Alexander; Shubha Srinivasan

doi:10.1016/j.hlc.2023.01.017

Gene Therapy for Paediatric Homozygous Familial Hypercholesterolaemia

Heart Lung Circ. 2023 Jul;32(7):769-779. doi: 10.1016/j.hlc.2023.01.017. Epub 2023 Apr 1.

Authors

Lara E Graves¹, Ari Horton², Ian E Alexander³, Shubha Srinivasan⁴

Affiliations

¹ 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. Electronic address: lara.graves@health.nsw.gov.au.
² 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.
³ 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.
⁴ 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.

PMID: 37012174
DOI: 10.1016/j.hlc.2023.01.017

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.

Keywords: Gene therapy; Genomic editing; Homozygous familial hypercholesterolaemia.

Publication types

Review

MeSH terms

Adolescent
Adult
Atherosclerosis* / genetics
Child
Genetic Therapy / methods
Homozygous Familial Hypercholesterolemia*
Humans
Hyperlipoproteinemia Type II* / epidemiology
Hyperlipoproteinemia Type II* / genetics
Hyperlipoproteinemia Type II* / therapy
Mutation
Phenotype