Composition and Methods for Treatment of Primary Ciliary Dyskinesia

a ciliary dyskinesia and composition technology, applied in the field of composition and methods for treating primary ciliary dyskinesia, can solve the problems of life-threatening breathing problems, current pcd treatment is not available, and conventional gene therapy methods remain challenging, and achieve the effect of effective delivery to target tissues

Inactive Publication Date: 2022-03-24
TRANSLATE BIO INC
View PDF0 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods and compositions for delivering mRNA to target tissues in vivo for the treatment of primary ciliary dyskinesia (PCD). The invention is based on the discovery that DNAH5 mRNA can be successfully encapsulated in a liposome and delivered to target tissues in vivo. The liposome can contain cationic lipids, non-cationic lipids, and PEG-modified lipids. The DNAH5 mRNA can be codon optimized and modified nucleotides can be used. The technical effects of the invention include effective delivery of mRNA to target tissues and reduction of symptoms or features of PCD.

Problems solved by technology

Chronic respiratory tract infections can result in condition called bronchiectasis, which damages the passages, called bronchi, and can cause life-threatening breathing problems.
There is currently no cure for PCD.
However, due to the large size of DNAH5 conventional gene therapy methods remain challenging.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Composition and Methods for Treatment of Primary Ciliary Dyskinesia
  • Composition and Methods for Treatment of Primary Ciliary Dyskinesia
  • Composition and Methods for Treatment of Primary Ciliary Dyskinesia

Examples

Experimental program
Comparison scheme
Effect test

example 1

Liposome Formulations for DNAH5 mRNA Delivery and Expression

[0309]This example provides exemplary liposome formulations for effective delivery and expression of hDNAH5 mRNA in vivo.

[0310]Lipid Materials

[0311]The formulations described in the following Examples, unless otherwise specified, contain a multi-component lipid mixture of varying ratios employing one or more cationic lipids, helper lipids (e.g., non-cationic lipids and / or cholesterol lipids) and PEGylated lipids designed to encapsulate human dynein axonemal heavy chain 5 (hDNAH5) mRNA. Unless otherwise specified, the multi-component lipid mixture used in the following Examples were ethanolic solutions of an imidazole cholesterol ester (“ICE”) cationic lipid, a non-cationic lipid such as DOPE, and a PEGylated lipid such as DMG-PEG2K.

[0312]Messenger RNA Material

[0313]Codon-optimized hDNAH5 messenger RNA was synthesized by in vitro transcription from a plasmid DNA template encoding the gene. Following in vitro transcription, a...

example 2

dministration and Delivery of hDNAH5 mRNA to the Lung and Expression of hDNAH5 Protein

[0316]This example illustrates exemplary methods of administering hDNAH5 mRNA-loaded liposome nanoparticles and methods for analyzing delivered mRNA and subsequently expressed hDNAH5 protein in lung epithelium in vivo.

[0317]The studies in this Example were performed using male 129S1 / SvimJ mice, which were of approximately 10-12 weeks of age. Three groups of mice (each n=5) were exposed by a single intratracheal aerosol administration via Microsprayer® (50 μL / animal) a test article (Groups 1 and 2) or a control. The test article for Group 1 was 10 μg / animal of MRT-1 hDNAH5 mRNA prepared as described in Example 1. The test article for Group 2 was 10 μg / animal (unless otherwise specified) of hDNAH5-GFP mRNA (i.e., a sequence including both MRT1 hDNAH5 mRNA and green fluorescent protein (GFP) mRNA) prepared as described in Example 1. The control included either saline administered at the same volume or...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal heavy chain 5 (DNAH5) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAH5 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims benefit of, and priority to, U.S. Provisional Patent Application Ser. No. 62 / 789,414 filed on Jan. 7, 2019, the contents of which are incorporated herein in its entiretyINCORPORATION-BY-REFERENCE OF SEQUENCE LISTING[0002]The contents of the text file named “MRT-2060WO_ST25.txt” which was created on Jan. 6, 2020 and is 504 KB in size, are hereby incorporated by reference in its entirety.BACKGROUND[0003]Primary ciliary dyskinesia (PCD) is an auto recessive disorder characterized by abnormal cilia and flagella that are found in the linings of the airway, the reproductive system, and other organs and tissues. PCD occurs in approximately 1 in 16,000. Symptoms are present as early as at birth, with breathing problems, and the affected individuals develop frequent respiratory tract infections beginning in early childhood. People with PCD also have year-round nasal congestion and chronic cough. Chronic respiratory tract in...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K9/127A61K31/711A61P11/00
CPCA61K9/1272A61P11/00A61K31/711A61K31/713C07K14/47A61K9/1271A61K9/0053A61K38/1709A61K31/7105
InventorDIAS, ANUSHAPAREKH, DARSHANDUBINS, JEFFREY S.COBAUGH, CHRISTIANKARVE, SHRIRANGPATEL, ZARNADUNAJ, SARA J.DEROSA, FRANKHEARTLEIN, MICHAEL
OwnerTRANSLATE BIO INC