Animal model of mucopolysaccharidoses type IVA

Patent metadata

Field	Value
Publication number	US-12201095-B2
Application number	US-201917293653-A
Country	US
Kind code	B2
Filing date	Nov 14, 2019
Priority date	Nov 15, 2018
Publication date	Jan 21, 2025
Grant date	Jan 21, 2025

Abstract

The present invention provides a new animal model for mucopolysaccharidosis type IVA or Morquio A syndrome and to methods of generating the animal model and uses thereof.

First claim

The invention claimed is:

1. A genetically modified non-human animal model of mucopolysaccharidoses type IVA or Morquio A syndrome comprising a missense mutation in the endogenous Galns gene, wherein said missense mutation is characterized by a substitution of cytosine (C) for thymine (T) at position 1162 (1162 C>T) in a nucleotide sequence as set forth in SEQ ID NO: 3 or a mutation in the amino acid sequence as set forth in SEQ ID NO: 4 consisting of a substitution of arginine (R) for cysteine (C) at position 388 (R388C), wherein said model expresses at least one phenotype associated with mucopolysaccharidoses type IVA or Morquio A syndrome, and wherein the non-human animal model is a rat model.

2. The non-human animal model according to claim 1 , wherein said at least one phenotype is dysostosis multiplex.

3. The non-human animal model according to claim 2 , wherein said dysostosis multiplex comprises reduced body length and/or bone length compared to wild-type animals.

4. The non-human animal model according to claim 2 , wherein said non-human animal model additionally expresses a phenotype selected from osteoarthritis, thin tooth enamel, dental fragility, malocclusion, and combinations thereof.

5. A cell line derived from a non-human animal model according to claim 1 .

6. A method for determining the effect of a compound on the animal model according to claim 1 , comprising:
i) placing into contact said animal model with said compound and
ii) detecting the presence or absence of a physiological, histological or morphological change in said animal as a response to said compound.

7. A method for evaluating the efficacy of a pharmaceutical composition or compound, said method comprising the steps of
i) providing the non-human animal model of claim 1 ; and
ii) evaluating the effect on said non-human animal model of a treatment with said pharmaceutical composition or compound.

8. A method for evaluating the effect of a treatment of mucopolysaccharidoses type IVA or Morquio A syndrome, said method comprising the steps of
i) providing the non-human animal model of claim 1 with a pharmaceutical composition or compound to be tested,
ii) evaluating the effect observed on said model treated with a pharmaceutical composition or compound.

Assignees

• Esteve Pharmaceuticals Sa
• Univ Barcelona Autonoma

Inventors

• Bosch-Tubert Maria-Fátima
• Bertolin-Galvez Joan
• Garcia-Martinez Miguel
• Sanchez-Clares Victor
• Pujol-Altarriba Anna-Maria

Classifications

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• A01K2267/0306

  Animal model for genetic diseases · CPC title

• A01K2227/105

  Murine · CPC title

• A01K2217/075

  inducing loss of function, i.e. knock out · CPC title

• C12Y301/06004

  N-Acetylgalactosamine-6-sulfatase (3.1.6.4) · CPC title