A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia

@article{Grossman1995APS,
  title={A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia},
  author={Mariann Grossman and Daniel J. Rader and David W M Muller and Daniel M. Kolansky and Karen Kozarsky and Bernard J. Clark and Evan A. Stein and Paul J. Lupien and H. Bryan Jr. Brewer and Steven E Raper and James M. Wilson},
  journal={Nature Medicine},
  year={1995},
  volume={1},
  pages={1148-1154}
}
The outcome of the first pilot study of liver-directed gene therapy is reported here. Five patients with homozygous familial hypercholesterolaemia (FH) ranging in age from 7 to 41 years were enrolled; each patient tolerated the procedure well without significant complications. Transgene expression was detected in a limited number of hepatocytes of liver tissue harvested four months after gene transfer from all five patients. Significant and prolonged reductions in low density lipoprotein (LDL… 
Recent Developments in Gene Therapy for Homozygous Familial Hypercholesterolemia
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A recombinant adeno-associated virus vector carrying a low-density lipoprotein receptor (LDLR) transgene which has recently entered phase 1/2a testing is discussed and a summary of key gene therapy approaches for HoFH in pre-clinical development is included, including RNA silencing of HMG-CoA reductase and induced pluripotent stem cell transplant therapy.
LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives
TLDR
Progress made in the 18 years since the first ex vivo clinical trial for gene therapy of FH is reviewed, with emphasis on the development, design, performance and limitations of viral based gene transfer vectors used in studies to ameliorate the effects of LDLR deficiency.
Review of the scientific evolution of gene therapy for the treatment of homozygous familial hypercholesterolaemia: past, present and future perspectives
TLDR
The genetic basis of the FH disease is reviewed, paying special attention to the severe HoFH as well as the challenges in its diagnosis and clinical management, and the current therapies for this disease are discussed.
Effective treatment of familial hypercholesterolaemia in the mouse model using adenovirus–mediated transfer of the VLDL receptor gene
TLDR
This work evaluated an alternative strategy of ectopic expression in the liver of the very low density lipoprotein (VLDL) receptor, which is homologous to the LDL receptor but has a different pattern of expression.
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Systemic gene therapy for cardiovascular disease.
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The current status of gene therapy and recent advances that will likely affect the clinical application of gene Therapy for the treatment of FH are discussed.
Autologous Gene and Cell Therapy Provides Safe and Long-Term Curative Therapy in A Large Pig Model of Hereditary Tyrosinemia Type 1
TLDR
It is concluded that hepatocyte-directed ex-vivo gene therapy is a rational choice for further exploration as an alternative therapeutic approach to whole organ transplantation for metabolic liver disease, including HT1.
Bile-duct proliferation as an unexpected side-effect after AAV2-LDLR gene transfer to rabbit liver
TLDR
A gene therapy protocol for FH using AAV2, AAV9 and lentiviral vectors is developed and safety and efficacy in LDL receptor deficient Watanabe Heritable Hyperlipidemic rabbits are tested and it is shown that LV-LDLR produced a significant long-lasting decrease in total serum cholesterol.
Gene Therapy of Familial Hypercholesterolemia
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These patients suffer from serum cholesterol levels between 500–1200 mg/100 ml (6–8 fold increased LDL-cholesterol) and develop severe atherosclerosis, experience myocardial infarctions during childhood and have a markedly reduced life expectancy.
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References

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TLDR
The treatment of a 29 year old woman with homozygous FH by ex vivo gene therapy directed to liver represents the first report of human gene therapy in which stable correction of a therapeutic endpoint has been achieved.
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TLDR
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TLDR
The potential efficacy of gene therapy for FH is supported by a series of studies performed in the Watanabe Heritable Hyperlipidemic rabbit in which it has achieved metabolic improvement and the genetically corrected cells were transplanted into the animal from which they were derived.
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TLDR
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TLDR
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