title: Recent Developments in Gene Therapy for Homozygous Familial Hypercholesterolemia.
abstract: Homozygous familial hypercholesterolemia (HoFH) is a life-threatening Mendelian disorder with a mean life expectancy of 33 years despite maximally tolerated standard lipid-lowering therapies. This disease is an ideal candidate for gene therapy, and in the last few years, a number of exciting developments have brought this approach closer to the clinic than ever before. In this review, we discuss in detail the most advanced of these developments, a recombinant adeno-associated virus (AAV) vector carrying a low-density lipoprotein receptor (LDLR) transgene which has recently entered phase 1/2a testing. We also review ongoing development of approaches to enhance transgene expression, improve the efficiency of hepatocyte transduction, and minimize the AAV capsid-specific adaptive immune response. We include a summary of key gene therapy approaches for HoFH in pre-clinical development, including RNA silencing of t﻿he gene encoding HMG-CoA reductase (HMGCR) and induced pluripotent stem cell transplant therapy.
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ezim
authors.initials: E
authors.lastname: Ajufo
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. mcuchel@upenn.edu.
authors.forename: Marina
authors.initials: M
authors.lastname: Cuchel
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism
chemical_list: D011973:Receptors, LDL
keywords: Adeno-associated virus (AAV); Adenovirus; Gene therapy; Homozygous familial hypercholesterolemia; LDL receptor; iPSC