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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
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Recent Developments in Gene Therapy for Homozygous Familial Hypercholesterolemia

Ezim Ajufo1, Marina Cuchel2

  • 1Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Current Atherosclerosis Reports
|March 17, 2016
PubMed

Insights

Gene therapy offers new hope for Homozygous familial hypercholesterolemia (HoFH), a severe genetic disorder. Advanced treatments, including AAV vector gene therapy targeting the LDLR gene, are progressing towards clinical application.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cardiovascular Medicine

Background:

  • Homozygous familial hypercholesterolemia (HoFH) is a severe, life-threatening Mendelian disorder.
  • Standard lipid-lowering therapies offer limited efficacy, resulting in a mean life expectancy of only 33 years.

Purpose of the Study:

  • To review the latest advancements in gene therapy for HoFH.
  • To detail the progress of adeno-associated virus (AAV) vector-based gene therapy utilizing the low-density lipoprotein receptor (LDLR) transgene.
  • To summarize other preclinical gene therapy strategies for HoFH.

Main Methods:

  • Review of current gene therapy research and clinical trials for HoFH.
  • Detailed examination of AAV vector technology for LDLR gene delivery.
  • Exploration of methods to optimize transgene expression and hepatocyte transduction.
  • Assessment of strategies to mitigate AAV capsid-specific immune responses.

Main Results:

  • A recombinant AAV vector carrying an LDLR transgene has entered Phase 1/2a clinical trials.
  • Ongoing research focuses on enhancing transgene expression and transduction efficiency.
  • Strategies are being developed to minimize adaptive immune responses to AAV capsids.

Conclusions:

  • Gene therapy, particularly AAV-mediated LDLR gene transfer, represents a promising therapeutic avenue for HoFH.
  • Further development is focused on optimizing delivery, expression, and safety profiles.
  • Preclinical approaches like RNA silencing and stem cell therapy also show potential for treating HoFH.

Keywords:
Adeno-associated virus (AAV)AdenovirusGene therapyHomozygous familial hypercholesterolemiaLDL receptoriPSC

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