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Treatment of hyperbilirubinemia

a technology of bilirubinemia and nucleic acid sequence, which is applied in the direction of transferases, peptide/protein ingredients, skeletal/connective tissue cells, etc., can solve the problems of loss of efficacy, potential exposure of patients to life-threatening spikes, and lethal disease, so as to improve the expression of transgenes and improve the immunogenicity of constructs. , the effect of reducing the risk of life-threatening spikes

Pending Publication Date: 2019-12-12
GENETHON +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The approach significantly reduces bilirubin levels and improves the therapeutic efficacy by increasing protein expression and minimizing immune response, offering a promising curative treatment for Crigler-Najjar syndrome and related hyperbilirubinemia conditions.

Problems solved by technology

Nonetheless patients are potentially exposed to the risk of life-threatening spikes in bilirubin in blood and liver transplantation remains the only curative treatment.
In its most severe form, the disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth.
Despite the availability of a therapy, CN remains an unmet medical need for a number of reasons including loss of efficacy of phototherapy during growth, poor compliance due to the limitation of phototherapy itself (which needs to be carried on for 10-12 hours each day), and occurrence of pathological liver changes over time, which may require liver transplantation.

Method used

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  • Treatment of hyperbilirubinemia
  • Treatment of hyperbilirubinemia
  • Treatment of hyperbilirubinemia

Examples

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examples

[0064]The invention is further described in detail by reference to the following experimental examples and the attached figures. These examples are provided for purposes of illustration only, and are not intended to be limiting.

Material and Methods

Codon Optimization and AAV Vector Construct:

[0065]The UGT1A1 underwent codon optimization according to several different algorithms. Additionally, removal of cryptic transcription start sites was implemented throughout the construct. The resulting constructs were either introduced into expression plasmids, or packaged into AAV serotype 8 vectors and tested in vitro and in vivo (rats and mice) for potency.

[0066]The following abbreviations are used throughout this experimental part for these constructs:[0067]WT.0: wild-type UGT1A1 transgene and the wild-type HBB2 intron (SEQ ID NO:5);[0068]WT: wild-type UGT1A1 transgene and the optimized version of the HBB2 intron with some ARFs removed (SEQ ID NO:6);[0069]v2 (or v2.0): comprises codon-optim...

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Abstract

The invention relates to a nucleic acid sequence useful in the treatment of hyperbilirubinemia, in particular in the treatment of Crigler-Najjar syndrome. More particularly, the nucleic acid sequence of the present invention is a codon-optimized UGT1A1 coding sequence.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 15 / 303,834, filed Oct. 13, 2016, which is the U.S. national stage application of International Patent Application No. PCT / EP2015 / 059099, filed Apr. 27, 2015.[0002]The Sequence Listing for this application is labeled “Seq-List.txt” which was created on Sep. 5, 2016 and is 16 KB. The entire content of the sequence listing is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0003]The invention relates to a nucleic acid sequence useful in the treatment of hyperbilirubinemia, in particular in the treatment of Crigler-Najjar syndrome. More particularly, the nucleic acid sequence of the present invention is a codon-optimized human UGT1A1 coding sequence.BACKGROUND OF THE INVENTION[0004]Crigler-Najjar syndrome (CN) is an autosomal recessive disorder with severe unconjugated hyperbilirubinemia due to deficiency of bilirubin UDP-glucuronosyltransferase isozyme 1A1...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/45A61K48/00C12N9/10C12N15/86C12N7/00C12N5/07C12N5/077
CPCC12N15/86C12N7/00C12Y204/01017A61K48/0066A61K48/0058C12N2750/14143A61K38/45C12N9/1051C12N2830/008C12N2830/42A61P1/16
Inventor MINGOZZI, FEDERICORONZITTI, GIUSEPPECOLLAUD, FANNYMURO, ANDRÉSBORTOLUSSI, GIULIA
Owner GENETHON
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