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Improved molecular platform for the gene therapy of rare diseases by liver protein secretion
- Source :
- European Journal of Medical Genetics, European Journal of Medical Genetics, 2018, 61 (11), pp.723-728. ⟨10.1016/j.ejmg.2018.04.010⟩, European Journal of Medical Genetics, Elsevier, 2018, 61 (11), pp.723-728. ⟨10.1016/j.ejmg.2018.04.010⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- International audience; Many rare monogenic diseases are treated by protein replacement therapy, in which the missing protein is repetitively administered to the patient. However, in several cases, the missing protein is required at a high and sustained level, which renders protein therapy far from being adequate. As an alternative, a gene therapy treatment ensuring a sustained effectiveness would be particularly valuable. Liver is an optimal organ for the secretion and systemic distribution of a therapeutic transgene product. Cutting edge non-viral gene therapy tools were tested in order to produce a high and sustained level of therapeutic protein secretion by the liver using the hydrodynamic delivery technique. The use of S/MAR matrix attachment region provided a slight, however not statistically significant, increase in the expression of a reporter gene in the liver. We have selected the von Willebrand Factor (vWF) gene as a particularly challenging large gene (8.4 kb) for liver delivery and expression, and also because a high vWF blood concentration is required for disease correction. By using the optimized miniplasmid pFAR free of antibiotic resistance gene together with the Sleeping Beauty transposon and the hyperactive SB100X transposase, we have obtained a sustainable level of vWFblood secretion by the liver, at 65% of physiological level. Our results point to the general use of this plasmid platform using the liver as a protein factory to treat numerous rare disorders by gene therapy.
- Subjects :
- 0301 basic medicine
[SDV.BIO]Life Sciences [q-bio]/Biotechnology
VON-WILLEBRAND-FACTOR
Genetic enhancement
Transgene
Transposases
VECTOR
Bioinformatics
03 medical and health sciences
DELIVERY
0302 clinical medicine
Protein replacement therapy
Rare Diseases
Von Willebrand factor
S/MAR ELEMENT
PLASMID DNA
von Willebrand Factor
Genetics
Medicine
Humans
EPISOMAL TRANSGENE EXPRESSION
HUMAN ALPHA-1-ANTITRYPSIN
Gene
Genetics (clinical)
Transposase
Reporter gene
SLEEPING-BEAUTY
biology
business.industry
General Medicine
Genetic Therapy
Sleeping Beauty transposon system
3. Good health
[SDV.BIO] Life Sciences [q-bio]/Biotechnology
030104 developmental biology
Liver
HEMOPHILIA-B
030220 oncology & carcinogenesis
biology.protein
DNA Transposable Elements
EXPRESSION IN-VIVO
business
Subjects
Details
- Language :
- English
- ISSN :
- 17697212
- Database :
- OpenAIRE
- Journal :
- European Journal of Medical Genetics, European Journal of Medical Genetics, 2018, 61 (11), pp.723-728. ⟨10.1016/j.ejmg.2018.04.010⟩, European Journal of Medical Genetics, Elsevier, 2018, 61 (11), pp.723-728. ⟨10.1016/j.ejmg.2018.04.010⟩
- Accession number :
- edsair.doi.dedup.....a11b3a3591db063964811d13a3649c9b