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Methods for treating alpha-1 antitrypsin deficiency (AATD)

A technology for antitrypsin and deficiency, applied in gene therapy, biochemical equipment and methods, DNA/RNA fragments, etc.

Pending Publication Date: 2022-03-22
ARROWHEAD RES CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no clinically approved treatments to prevent the onset of liver disease caused by AATD, slow the progression of liver disease caused by AATD, or otherwise treat liver disease caused by AATD

Method used

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  • Methods for treating alpha-1 antitrypsin deficiency (AATD)
  • Methods for treating alpha-1 antitrypsin deficiency (AATD)
  • Methods for treating alpha-1 antitrypsin deficiency (AATD)

Examples

Experimental program
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Effect test

Embodiment 1

[0136] Example 1. Synthesis and formulation of AAT RNAi drug substance (ADS-001)

[0137] AAT RNAi drug substances suitable for use in the methods disclosed herein can be synthesized as known in the art using standard phosphoramidite techniques based on solid phase oligonucleotide synthesis. A commercially available oligonucleotide synthesizer (e.g., (Bioautomation) or (Bioautomation)). Available in controlled pore glass (CPG, or Synthesis was performed on solid supports made from Prime Synthesis, Aston, PA, USA). The monomer at the 3' end of the corresponding chain can be attached to a solid support as the starting point for the synthesis. All RNAs, 2'-modified RNA phosphoramidites and inverted abasic phosphoramidites are commercially available. Targeting group-containing phosphoramidites suitable for addition to the 5' end of the sense strand can be synthesized. Standard cleavage, deprotection, purification and annealing steps may be utilized as known in the art. ...

Embodiment 2

[0138] Example 2. Phase I clinical trial of AAT RNAi drug substance (ADS-001) in normal healthy human volunteers (NHV).

[0139] A phase 1 single and multiple dose escalation study was conducted to evaluate the safety, tolerability, pharmacokinetics and effects of an AAT RNAi drug substance (ADS-001) on serum AAT levels in healthy volunteers (NHV). The study subject population includes BMI at 19.0kg / m 2 with 35.0kg / m 2 Healthy adult men and women between the ages of 18-52.

[0140] NHV subjects were divided into a total of seven cohorts. Cohorts 1 to 4 were randomly assigned to receive single ascending doses of 35 mg (cohort 1 ) and multiple ascending doses of 100 mg (cohort 2 ), 200 mg (cohort 3 ) and 300 mg (cohort 3 ) administered as a subcutaneous injection. 4) AAT RNAi drug substance or placebo (4 groups active: 4 groups placebo). Cohorts 1 to 4 were double-blind. Cohorts 2b, 3b and 4b were open label consisting of 4 subjects receiving single doses of 100, 200 and 30...

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Abstract

Methods of treating alpha-1 antitrypsin deficiency (AATD) in a human patient in need thereof using a pharmaceutical composition comprising an AAT RNAi agent are described. The pharmaceutical compositions comprising AATRNAi agents disclosed herein treat liver diseases associated with AAT deficiency, such as chronic hepatitis, cirrhosis, increased risk of hepatocellular carcinoma, elevated transaminase, cholestasis, fibrosis, outbreak liver failure, and other liver-related diseases when administered to a human patient in need thereof.

Description

[0001] sequence listing [0002] This application contains a Sequence Listing, which has been filed in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy is named 30674_WO1_SequenceListing.txt and is 6kb in size. [0003] field of invention [0004] Disclosed herein is the use of a pharmaceutical composition comprising an RNA interference (RNAi) agent that inhibits expression of the alpha-1 antitrypsin gene to treat alpha-1 antitrypsin deficiency (AATD) in a human subject (including treating symptoms caused by AATD and disease) method. Background technique [0005] Alpha-1 antitrypsin (AAT, alpha 1-antitrypsin or A1AT) is a protease inhibitor belonging to the serine protease inhibitory protein (serpin) superfamily encoded by the SERPINA1 gene in humans. The normal AAT protein is a circulating glycoprotein protease inhibitor synthesized primarily in the liver by hepatocytes and secreted into the blood. A known physiological function of AAT ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113A61K31/7125A61P1/16A61P11/00A61K31/713A61K31/712
CPCA61K31/713A61P1/16A61P11/00C12N15/113A61K45/06C12N2310/344C12N2310/3515C12N2310/321C12N2310/322C12N2310/343C12N2310/332C12N2310/315C12N2310/346A61K9/0019A61K47/02A61K2300/00C12N2310/3521C12N2310/3533A61K48/00
Inventor B·吉文D·克里斯蒂安松J·汉米尔顿李珍朱锐C·伍德尔裴涛
Owner ARROWHEAD RES CORP
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