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Gene-Editing Therapies for Alpha-1-Antitrypsin Deficiency


Alpha-1-antitrypsin deficiency is a disease caused by mutations in the A1AT gene. Patients with this disease experience progressive liver failure, as well as lung irritation and damage. Most patients with AAT deficiency are homozygous for the Glu342Lys mutation, which causes cells to produce a form of AAT that aggregates into toxic intracellular polymers.

Our scientists developed a method for treating AAT deficiency by editing the A1AT gene using mRNA to express gene-editing proteins.

Gene-Editing Therapies for Alpha-1-Antitrypsin Deficiency is protected by U.S. Patent Number 10,576,167 (with additional patents pending in the U.S. and in other countries). Of note, certain claims of the granted patent are not limited by specific target sequence, formulation, or route of administration.

Example Applications

  • Develop a single therapy for the majority of patients – most AAT deficiency patients share the same mutation (Glu342Lys)
  • Avoid gene repair or gene insertion by using a combination therapy that includes AAT protein replacement
  • Express gene-editing proteins in vivo or harvest cells, gene-edit ex vivo and infuse gene-edited cells
  • Combine with Factor’s mRNA Cell Reprogramming technology to generate a clonal line of gene-corrected pluripotent stem cells

Figure 1. Gene editing of the A1AT gene in primary human cells using mRNA encoding gene-editing proteins.

Representative Claim

U.S. Pat. No. 10,576,167
A method for treating alpha-1 antitrypsin (A1AT) deficiency comprising administering an effective
amount of a synthetic RNA encoding a gene-editing protein capable of creating a double strand break
in A1AT to a subject, wherein the synthetic RNA comprises one or more non-canonical nucleotides that
avoid substantial cellular toxicity, and
wherein the gene-editing protein comprises:
(i) a DNA-binding domain comprising a plurality of repeat sequences and at least one of the repeat
sequences comprises the amino acid sequence: LTPvQVVAIAwxyzGHGG (SEQ ID NO: 629)
and is between 36 and 39 amino acids long, wherein:
“v” is Q, D or E,
“w” is S or N,
“x” is H, N, or I,
“y” is D, A, I, N, G, H, K, S, or null, and
(SEQ ID NO: 631); and
(ii) a nuclease domain comprising a catalytic domain of a nuclease.