# US 11,591,614 B2 · Gene therapy for ceroid lipofuscinoses

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- Number: US 11,591,614 B2
- Document ID: US11591614B2
- Status: Granted
- Kind: B2
- Application number: 16/611,512
- Filed: 2018-05-11
- Published: 2020-07-30
- Granted: 2023-02-28
- Earliest claimed: 2017-05-11
- Assignees: The Trustees of the University of Pennsylvania
- Applicants: The Trustees of the University of Pennsylvania
- Inventors: James M. Wilson; Nathan Katz; Christian Hinderer; Juliette Hordeaux
- Web page: https://patentgrep.com/patent/US11591614B2

## CPC

- C12N 9/6421: {from mammals}
- C12N 15/86: Viral vectors
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C12N 9/485: {Exopeptidases (3.4.11-3.4.19)}
- A01K 2227/105: Murine
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C12N 2710/16143: viral genome or elements thereof as genetic vector
- C12N 2750/14143: viral genome or elements thereof as genetic vector
- C12Y 304/14009: Tripeptidyl-peptidase I (3.4.14.9)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- C12Y: ENZYMES

## Abstract

Provided herein are methods and compositions for treatment of Batten disease. Such compositions include a recombinant adeno-associated virus (rAAV), said rAAV comprising an AAV capsid, and a vector genome packaged therein, said vector genome comprising (a) an AAV 5′ inverted terminal repeat (ITR) sequence; (b) a promoter; (c) a CLN2 coding sequence encoding a human TPP1; (d) an AAV 3′ ITR.

## Claims

### Claim 1

A recombinant adeno-associated virus (rAAV), comprising an AAV capsid, and a vector genome packaged therein, said vector genome comprising:
(a) an AAV 5′ inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a CLN2 coding sequence encoding a human TPP1; and
(d) an AAV 3′ ITR sequence,
wherein the CLN2 coding sequence shares 95% or greater identity with the nucleotide sequence set forth in SEQ ID NO: 3.

### Claim 2 (depends on 1)

The rAAV according to claim 1, wherein the coding sequence of (c) comprises nucleotides 1 to 1689 of SEQ ID NO: 3.

### Claim 3 (depends on 1)

The rAAV according to claim 1, wherein the AAV capsid is an AAV9 capsid or a variant thereof.

### Claim 4 (depends on 1)

The rAAV according to claim 1, wherein the promoter is a chicken beta actin (CBA) promoter.

### Claim 5 (depends on 1)

The rAAV according to claim 1, wherein the promoter is a hybrid promoter comprising a CBA promoter sequence and cytomegalovirus enhancer elements.

### Claim 6 (depends on 1)

The rAAV according to claim 1, wherein the AAV 5′ ITR sequence and/or AAV3′ ITR sequence is from AAV2.

### Claim 7 (depends on 1)

The rAAV according to claim 1, wherein the vector genome further comprises a polyA.

### Claim 8 (depends on 7)

The rAAV according to claim 7, wherein the polyA is a synthetic polyA or from bovine growth hormone (bGH), human growth hormone (hGH), SV40, rabbit β-globin (RGB), or modified RGB (mRGB).

### Claim 9 (depends on 1)

The rAAV according to claim 1, wherein the vector genome further comprises an intron.

### Claim 10 (depends on 9)

The rAAV according to claim 9, wherein the intron is from CBA, human beta globin, IVS2, SV40, bGH, alpha-globulin, beta-globulin, collagen, ovalbumin, or p53.

### Claim 11 (depends on 1)

The rAAV according to claim 1, wherein the vector genome further comprises an enhancer.

### Claim 12 (depends on 11)

The rAAV according to claim 11, wherein the enhancer is a CMV enhancer, an RSV enhancer, an APB enhancer, ABPS enhancer, an alpha mic/bik enhancer, TTR enhancer, en34, or ApoE.

### Claim 13 (depends on 1)

The rAAV according to claim 1, wherein the vector genome is about 3 kilobases to about 5.5 kilobases in size.

### Claim 14 (depends on 13)

The rAAV according to claim 13, wherein the vector genome is about 4 kilobases in size.

### Claim 15 (depends on 1)

A composition comprising the rAAV of claim 1 and a pharmaceutically acceptable carrier or an excipient suitable for delivery to the central nervous system.

### Claim 16 (depends on 1)

A composition comprising the rAAV of claim 1 and a pharmaceutically acceptable carrier or an excipient suitable for intracerebroventricular (ICV) delivery.

### Claim 17

An aqueous suspension suitable for administration to subject having Batten disease, said suspension comprising an aqueous suspending liquid and a recombinant adeno-associated virus (rAAV) useful as a therapeutic for Batten disease, said rAAV having an AAV capsid, and having packaged therein a vector genome comprising:
(a) an AAV 5′ inverted terminal repeat (ITR) sequence;
(b) a promoter;
(c) a CLN2 coding sequence encoding a human TPP1; and
(d) an AAV 3′ ITR sequence,
wherein the CLN2 coding sequence shares 95% or greater identity with the nucleotide sequence set forth in SEQ ID NO: 3.

### Claim 18 (depends on 17)

The suspension according to claim 17, wherein the suspension is suitable for intrathecal delivery.

### Claim 19 (depends on 17)

The suspension according to claim 17, wherein the suspension is suitable for intrathecal delivery selected from ICV and intrathecal lumbar (IT-L) injection.

### Claim 20 (depends on 17)

The suspension according to claim 17, wherein the suspension further comprises a surfactant, preservative, and/or buffer dissolved in the aqueous suspending liquid.

### Claim 21 (depends on 17)

The suspension according to claim 17, wherein the promoter is nt 3396 to nt 4061 of SEQ ID NO: 5 and the coding sequence encoding the human TPP1 is SEQ ID NO: 3.

### Claim 22 (depends on 17)

The suspension according to claim 17 wherein the AAV 5′ ITR sequence is nt 3199 to 3328 of SEQ ID NO: 5 and the AAV 3′ ITR sequence is nt 248 to 377 of SEQ ID NO: 5.

### Claim 23 (depends on 17)

The suspension according to claim 17, wherein the vector genome further comprises a polyA sequence of nt 33 to 159 of SEQ ID NO: 5.

### Claim 24 (depends on 17)

The suspension according to claim 17, wherein the rAAV capsid is an AAV9 capsid.

### Claim 25 (depends on 1)

A method of treating a subject having Batten disease with a therapeutically effective amount of the rAAV according to claim 1.

### Claim 26 (depends on 25)

The method according to claim 25, wherein the therapeutically effective amount is about 1×109 to about 1×1016 vector genomes in an aqueous suspension.

### Claim 27 (depends on 25)

The method according to claim 25, wherein the rAAV is administered intrathecally.

### Claim 28 (depends on 27)

The method according to claim 27, wherein the intrathecal administration is selected from ICV and intrathecal lumbar (IT-L) injection.

### Claim 29 (depends on 25)

The method according to claim 25, wherein said rAAV is administered in a dosage of from 1×109 to 1×1013 rAAV in a volume comprising about or at least 1 to 20 milliliters.

### Claim 30 (depends on 25)

The method according to claim 25, wherein said subject is human.