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Trans-splicing molecules

A trans-splicing and molecular technology, applied in the direction of splicing changes, genetic material components, organic active components, etc., can solve problems such as hindering the delivery of large nucleic acid molecules

Pending Publication Date: 2021-03-05
海鞘治疗有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, AAV vectors may have limitations dictated by viral biology, such as packaging size limitations, that may hinder the delivery of large nucleic acid molecules, such as those necessary to replace the ABCA4 gene or the CEP290 gene

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0283] Example 1. ABCA4

[0284] This example describes the development of ABCA4 trans-splicing molecules, for example, by screening for efficient binding sites within specific ABCA4 introns, the development of ABCA4 cell lines for testing trans-splicing molecules, and the testing of various ABCA4 trans-splicing Molecules to restore ABCA4 protein expression.

[0285] binding site screening

[0286] Screening of a series of binding domains configured to bind ABCA4 intron 19 (SEQ ID NO: 25) at sequential binding sites revealed a region of the 3' portion of ABCA4 intron 19 that is in 5' trans Preferentially effective in trans-splicing of splicing molecules—the region from nucleotides 990 to 2,174 of intron 19 ( figure 2 ). Binding sites ranging from 1,670 to 2,174, from 1,810 to 2,000, from 1,870 to 2,000, or from 1,920 to 2,000 nucleotides were revealed to be particularly efficient at mediating 5' trans-splicing of intron 19.

[0287] A suitable binding site for the 5' tran...

Embodiment 2

[0324] Example 2. CEP290

[0325] Screening of a series of binding domains configured to bind CEP290 intron 26 (SEQ ID NO: 85) at sequential binding sites revealed that the region of the 3' portion of CEP290 intron 26 is preferentially suited for 5' trans Trans-splicing of the splicing molecule - the region from nucleotides 4,980 to 5,838 of intron 26 ( Figure 22 ). Binding sites revealed to be in the range of nucleotides 5,348-5,838, 5,348-5,700, 5,400-5,600, 5,460-5,560, or 5,500 are particularly effective in mediating trans-splicing.

[0326] Figure 23Results of a similar screen for CEP290 intron 27 (SEQ ID NO: 86) are shown. Binding sites identified with nucleotides 120 to 680, 710 to 2,200, 2,670 to 2,910 are preferentially suitable for trans-splicing of 5' trans-splicing molecules. In particular, binding domains targeting binding sites in the range of nucleotides 790 to 2,100, nucleotides 1,020 to 1,630, or nucleotides 1,670 to 2,000 are efficient in trans-splicing...

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Abstract

The present invention features nucleic acid trans-splicing molecules (e.g., pre-mRNA trans- splicing molecules (RTMs)) capable of correcting one or more mutations in the ABCA4 gene or the CEP290 gene.Such molecules are useful in the treatment of disorders associated with mutations in ABCA4, such as Stargardt Disease (e.g., Stargardt Disease 1) and disorders associated with a mutation in CEP290, such as Leber congenital amourosis 10 (LCA 10). Also provided by the invention described herein are methods of using the nucleic acid trans-splicing molecules for correcting mutations in ABCA4 and CEP290 and for treating disorders associated with mutations in ABCA4 and CEP290, such as Stargardt Disease and LCA 10.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Application Serial Nos. 62 / 658,658 and 62 / 658,667, both filed April 17, 2018, the entire contents of which are hereby incorporated by reference in their entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on March 17, 2019, is named 51219-016WO2_Sequence_Listing_04.16.19_ST25 and is 608,489 bytes in size. technical field [0005] In general, the invention features ABCA4 and CEP290 trans-splicing molecules. Background technique [0006] Stargardt disease is a progressive eye disorder characterized by loss of central vision and color vision that can develop rapidly or over several years. Peripheral vision usually remains intact. Various mutations along the length of the ABCA4 gene...

Claims

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Application Information

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IPC IPC(8): A61K48/00C07K14/705
CPCC07K14/705C07K2319/85C07K2319/00C07K2319/71C12N15/113C12N15/1138C12N2310/20C12N2320/33C12N2320/34A61K31/7088A61P27/02C12N2750/14143
Inventor 菲利普·R·约翰逊布鲁斯·C·施奈普吉恩·贝内特斯科特·J·杜利克里希纳·贾瓦哈拉尔·费舍尔孙军伟
Owner 海鞘治疗有限公司
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