# US 11,027,024 B2 · Methods of delivery of transgenes for treating brain diseases

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- Number: US 11,027,024 B2
- Document ID: US11027024B2
- Status: Granted
- Kind: B2
- Application number: 15/578,170
- Filed: 2016-05-31
- Published: 2018-06-21
- Granted: 2021-06-08
- Earliest claimed: 2015-05-29
- Assignees: University of Iowa Research Foundation
- Applicants: University of Iowa Research Foundation
- Inventors: Beverly L. Davidson; Megan S. Keiser
- Web page: https://patentgrep.com/patent/US11027024B2

## CPC

- A61K 48/0058: {Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct}
- A61P 25/00: Drugs for disorders of the nervous system
- C07K 14/47: from mammals
- C12N 15/113: 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)}
- C12N 15/79: Vectors or expression systems specially adapted for eukaryotic hosts
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2310/531: Stem-loop; Hairpin
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N 2330/51: Specially adapted vectors
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present disclosure provides methods of treating a disease or delivering a therapeutic agent to a mammal comprising administering to the mammal's deep cerebella nuclei a recombinant adeno-associated virus (rAAV) particle comprising an AAV capsid protein and a vector comprising a nucleic acid encoding a therapeutic agent inserted between a pair of AAV inverted terminal repeats in a manner effective to infect the CNS cell of the non-rodent mammal such that the CNS cell expresses the therapeutic agent in the non-rodent mammal.

## Claims

### Claim 1

A method of delivering a therapeutic agent to a central nervous system (CNS) cell of a mammal, wherein the mammal exhibits Spinocerebellar Ataxia Type 1 (SCA1) disease, comprising directly injecting to the mammal's deep cerebella nuclei a recombinant adeno-associated virus (rAAV) particle comprising a nucleic acid encoding an AAV1 capsid protein and a nucleic acid encoding miRNA ataxin type 1 (Atxn1) inserted between a pair of AAV2 inverted terminal repeats in a manner effective to infect the CNS cell of the mammal such that the CNS cell expresses the therapeutic agent in the mammal, and wherein the therapeutic agent is the nucleic acid encoding the miRNA Atxn1, and wherein the rAAV particle comprises the nucleotide sequence as set forth in SEQ ID NO: 14 and the CNS cell is a cerebellar Purkinje cell or deep cerebella nuclei.

### Claim 2

A method of treating Spinocerebellar Ataxia Type 1 (SCA1) disease in a mammal, wherein the mammal exhibits Spinocerebellar Ataxia Type 1 (SCA1) disease, comprising directly injecting to the mammal's deep cerebella nuclei a recombinant adeno-associated virus (rAAV) particle comprising a nucleic acid encoding an AAV1 capsid protein and a nucleic acid encoding miRNA ataxin type 1 (Atxn1) inserted between a pair of AAV2 inverted terminal repeats in a manner effective to infect a central nervous system (CNS) cell of the mammal such that the CNS cell expresses the miRNA in the mammal, to treat Spinocerebellar Ataxia Type 1 (SCA1) disease, and wherein the miRNA reduces Atxn1 mRNA level, and wherein the rAAV particle comprises the nucleotide sequence as set forth in SEQ ID NO: 14, and the CNS cell is a cerebellar Purkinje cell or deep cerebella nuclei.

### Claim 3 (depends on 1)

The method of claim 1, wherein the mammal is a non-rodent mammal.

### Claim 4 (depends on 1)

The method of claim 1, wherein the non rodent mammal is a primate, horse, sheep, goat, pig, or dog.

### Claim 5 (depends on 4)

The method of claim 4, wherein the primate is human.

### Claim 6 (depends on 1)

The method of claim 1, wherein the method comprises directly injecting a plurality of the rAAV particles in a single dose to the mammal's deep cerebella nuclei.

### Claim 7 (depends on 6)

The method of claim 6, wherein the plurality of rAAV particles are directly injected at a dose of about 1-5 ml of 1×105-1×1016 vg/ml.

### Claim 8 (depends on 2)

The method of claim 2, wherein the mammal is a non-rodent mammal.

### Claim 9 (depends on 8)

The method of claim 8, wherein the non-rodent mammal is a primate, horse, sheep, goat, pig, or dog.

### Claim 10 (depends on 2)

The method of claim 2, wherein the rAAV particle is directly injected in a single dose to the mammal's deep cerebella nuclei.

### Claim 11 (depends on 2)

The method of claim 2, wherein the rAAV particle is directly injected at a dose of about 1-5 ml of 1×105-1×1016 vg/ml.

### Claim 12 (depends on 2)

The method of claim 2, wherein the Atxn1 mRNA level is reduced by at least 10% in the cerebellum, deep cerebella nuclei, brain stem (BS), and for thalamus.