RNAi induced huntingtin gene suppression

A technology of gene therapy and DNA sequence, applied in DNA/RNA fragment, gene therapy, genetic engineering, etc., can solve the problem of knocking down huntingtin gene

Active Publication Date: 2018-05-22
尤尼克尔生物制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Testing a large number of target sequences for efficient knockdown of the huntingtin gene

Method used

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  • RNAi induced huntingtin gene suppression
  • RNAi induced huntingtin gene suppression
  • RNAi induced huntingtin gene suppression

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Experimental program
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Embodiment approach

[0061] 1. A double-stranded RNA comprising a first RNA sequence and a second RNA sequence, wherein the first RNA sequence and the second RNA sequence are substantially complementary, wherein the first RNA sequence has at least 19 nucleotides The sequence length is basically complementary to SEQID NO.1.

[0062] 2. The double-stranded RNA according to embodiment 1, wherein the double-stranded RNA is capable of reducing the expression of the huntingtin gene.

[0063] 3. The double-stranded RNA according to embodiment 1 or 2, wherein said double-stranded RNA is comprised within a pre-miRNA scaffold, pri-miRNA scaffold, shRNA or siRNA, preferably within a pre-miRNA scaffold.

[0064]4. The double-stranded RNA according to any one of embodiments 1-3, wherein said first RNA sequence has a sequence length of at least 20 nucleotides, preferably at least 21 nucleotides.

[0065] 5. The double-stranded RNA according to any one of embodiments 1-4, wherein the first RNA sequence is fully...

Embodiment

[0078] miRNA scaffold expression constructs & siRNA

[0079] In order to construct the miRNA scaffold vector based on miR155, it will be combined with figure 1 The selected target sequence in the indicated HTT is fully complementary with a 21 nucleotide (bp) sequence embedded into the pri-mir of pcDNA6.2-GW / EmGFP-miR (Invitrogen, Carlsbad, CA) pVD-CMV-miHTT-155 ( Figure 2C Examples of expression cassette sequences are shown, and the pre-miRNA and pri-miRNA sequences contained in the expressed RNA are shown in Figure 2B and Figure 2F middle). Based on the instructions provided by Invitrogen (BLOCK-iT, Pol II miR RNAi expression vector kit, Verson E, June 22, 2007, 25-0857), through the BsaI site pairing in pcDNA6.2-GW / emGFP-mir155 Synthetic double-stranded oligonucleotides were annealed to design the pri-mir-155 construct. Using the Mfold software (Nucleic Acids Res. 31(13), 3406-15, (2003)), it was verified that Structures of all artificial pre-miRNAs encoded by miHtt...

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Abstract

The present invention provides for a double stranded RNA comprising a first RNA sequence and a second RNA sequence wherein the first and second RNA sequence are substantially complementary, wherein the first RNA sequence has a sequence length of at least 19 nucleotides and is substantially complementary to SEQ ID NO. 1. Said double stranded RNA is for use in inducing RNAi against Huntingtin exon 1sequences. The double stranded RNA of to the invention was capable of reducing neuronal cell death and huntingtin aggregates in an animal model.

Description

Background technique [0001] The huntingtin gene, also known as the HTT or HD (Huntington's disease) gene, encodes the huntingtin protein. The huntingtin gene is a large gene of approximately 13.5 kb (huntingtin approximately 350 kDa). Huntington's disease is an inherited neurodegenerative disorder caused by genetic mutations in the huntingtin gene. The genetic mutation involves a stretch of DNA called a CAG trinucleotide repeat in the huntingtin gene. Usually, the CAG segment in the human huntingtin gene is repeated many times, ie about 10-35 times. People with Huntington's disease have an enlarged number of CAG repeats in at least one allele. Affected individuals usually inherit the mutated allele from an affected parent. In rare cases, neither parent of an individual with Huntington's disease has the disease (sporadic HD). People with 36-39 CAG repeats may develop the signs and symptoms of Huntington's disease, while those with 40 or more CAG repeats almost always devel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113C12N15/11C12N15/864A61K31/713A61K48/00A61P25/14
CPCA61K31/713C12N2310/14C12N2310/3519C12N2310/531C12N2320/32C12N2330/51C12N15/113A61P25/00A61P25/14C12N2310/141
Inventor 帕夫林纳斯蒂芬诺娃·康斯坦丁诺娃亚娜·米尼亚利柯娃
Owner 尤尼克尔生物制药股份有限公司
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