Treatment of hyperbilirubinemia

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...

AI Technical Summary

Benefits of technology

[0009]Advantageously, the codon optimized nucleic acid of the invention provides for improved reduction in bilirubin levels and / or for decreased immunogenicity.

[0013]The inventors have shown that such a modified intron, in particular a modified HBB2 or FIX intron, has advantageous properties and can significantly improve the expression of the transgene. Furthermore, by decreasing the number of ARFs within the intron included within the construct of the invention, it is believed that the construct immunogenicity is also decreased.

[0030]The term “decreased immunogenicity” as applied to the codon-optimized UGT1A1 coding sequence or to the modified intron of the invention means that this codon-optimized gene or modified intron comprises a decreased number of potential alternative open reading frames (or ARFs) in either the intron, or the coding sequence, or both, thereby limiting the number of potential translation protein by-products, in particular from the coded mRNA, as compared to the wild-type cDNA or other UGT1A1 cDNA variants. In particular, decreased ARFs are those whose length spans over 50 bp and have a stop codon in frame with a start codon.

[0036]AAVs may be engineered using conventional molecular biology techniques, making it possible to optimize these particles for cell specific delivery of nucleic acid sequences, for minimizing immunogenicity, for tuning stability and particle lifetime, for efficient degradation, and for accurate delivery to the nucleus.

[0050]In a preferred embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the site of the injection.

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.

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