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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
  • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
  • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
  • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
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  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
• • C—CHEMISTRY; METALLURGY
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  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
  • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
  • C12N15/09—Recombinant DNA-technology
  • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
  • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
  • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
  • C12N15/86—Viral vectors
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
  • C07K2319/42—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation containing a HA(hemagglutinin)-tag
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/40—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation
  • C07K2319/43—Fusion polypeptide containing a tag for immunodetection, or an epitope for immunisation containing a FLAG-tag
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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  • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
  • C12N2750/00011—Details
  • C12N2750/14011—Parvoviridae
  • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
  • C12N2750/14122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• • C—CHEMISTRY; METALLURGY
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  • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
  • C12N2750/00011—Details
  • C12N2750/14011—Parvoviridae
  • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
  • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
  • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

• the present disclosure provides improved gene therapy vectors comprising a polynucleotide sequence encoding a LAMP-2 polypeptide, methods of use thereof, pharmaceutical compositions, and more.
• the disclosure provides recombinant AAV vectors having AAVrh74 serotype expressing LAMP-2A, LAMP-2B, or LAMP-2C for use as a therapeutic in, for example, Danon disease.
• FIG. 6B shows micrographs of semi-quantitative mRNA analysis by RNAscope in treated left ventricles.
• FIG. 8 shows micrographs of semi-quantitative mRNA analysis by RNAscope in treated gastrocnemius.
• FIG. 9 shows a bar graph of protein quantification in tissues most affected in Danon disease by ELISA.
• the transgene is codon-optimized for expression in a human host cell.
• the transgene coding sequence is modified, or“codon optimized” to enhance expression by replacing infrequently represented codons with more frequently represented codons.
• the coding sequence is the portion of the mRNA sequence that encodes the amino acids for translation. During translation, each of 61 trinucleotide codons are translated to one of 20 amino acids, leading to a degeneracy, or redundancy, in the genetic code.
• tRNAs each bearing an anticodon
• the expression cassette comprises operatively linked, in the 5’ to 3’ direction, a first inverted terminal repeat, an enhancer/promoter region, introns, a consensus optimal Kozak sequence, the transgene, a 3’ untranslated region including a full- length polyA sequence, and a second inverted terminal repeat, where the expression cassette comprises no start codon 5’ to the start codon of the transgene.
• GGGGAAC AAAGGCTGCGT GCGGGGT GT GTGCGT GGGGGGGT GAGC AGGGGGTG TGGGCGCGTCGGTCGGGCTGCAACCCCCCCTGCACCCCCCTCCCCGAGTTGCTGA
• the vector is an adeno-associated virus (AAV) vector.
• the expression cassette comprises ITR sequences selected from SEQ ID NOs: 13 and 14.
• the expression cassette comprises a polynucleotide sequence encoding LAMP -2 disclosed herein, e.g ., SEQ ID NOs: 15-17 or a sequence having at least 90%, at least 95%, at least 98%, or at least 99% identity to any of SEQ ID NOs: 15- 17.
• the gene therapy vectors can be viral or non-viral vectors.
• Illustrative non-viral vectors include, e.g. , naked DNA, cationic liposome complexes, cationic polymer complexes, cationic liposome-polymer complexes, and exosomes.
• viral vector include, but are not limited, to adenoviral, retroviral, lentiviral, herpesvirus and adeno-associated virus (AAV) vectors.
• the expression cassette comprising a polynucleotide sequence encoding one or more, two or more, or all three of SEQ ID NOs: 15-17.
• the expression cassette, AAV capsid gene, and/or helper genes are delivered to cells using transduction, transfection, electroporation, lipofection, and any other methods known in the art.
• the expression cassette, AAV capsid gene, and/or helper genes are delivered in a liposome or a lipid nanoparticle (LNP).
• the expression cassette, AAV capsid gene, and/or helper genes may be provide as DNA, e.g. on one or more plasmids, bacmids, or other DNA molecules.
• expression cassette, AAV capsid gene, and/or helper genes are delivery as RNA molecules.
• Gene delivery viral vectors useful in the practice of the present invention can be constructed utilizing methodologies well known in the art of molecular biology.
• viral vectors carrying transgenes are assembled from polynucleotides encoding the transgene, suitable regulatory elements and elements necessary for production of viral proteins, which mediate cell transduction.
• Such recombinant viruses may be produced by techniques known in the art, e.g ., by transfecting packaging cells or by transient transfection with helper plasmids or viruses.
• Typical examples of virus packaging cells include but are not limited to HeLa cells, SF9 cells (optionally with a baculovirus helper vector), 293 cells, etc.
• Herpesvirus-based system can be used to produce AAV vectors, as described in
• AAV is a 4.7 kb, single stranded DNA virus. Recombinant vectors based on AAV are associated with excellent clinical safety, since wild-type AAV is nonpathogenic and has no etiologic association with any known diseases. In addition, AAV offers the capability for highly efficient gene delivery and sustained transgene expression in numerous tissues.
• an “AAV vector” is meant a vector derived from an adeno-associated virus serotype, including without limitation, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAVrh. lO, AAVrh74, etc.
• Adeno-associated virus is single stranded DNA virus.
• the AAV genome is built of single-stranded deoxyribonucleic acid (ssDNA), either positive- or negative-sensed, which is about 4.7 kilobase long.
• the genome comprises inverted terminal repeats (ITRs) at both ends of the DNA strand, and two open reading frames (ORFs): rep and cap.
• ITRs inverted terminal repeats
• ORFs open reading frames
• the first, rep is composed of four overlapping genes encoding Rep proteins required for the AAV life cycle, and the second, cap , encodes three capsid proteins: VP1, VP2 and VP3.
• the cap gene is expressed as a messenger RNA (mRNA) from the p40 promoter of AAV.
• mRNA messenger RNA
• VP1 is expressed only from the 2.6 kb transcript and the VPl protein is 87 kilodaltons (kDa) in molecular weight.
• VP2 is expressed from an open reading frame that begins with an ACG codon, rather than a canonical AUG codon, due to the presence of an optimal Kozak sequence for translation initiation.
• VP2 is 72 kDa.
• VP3, only 62 kDa is expressed from the ATG sequence presence in the 2.3 kb transcript, as well as the 2.6 kb transcript.
• the relative abundances of VP1 :VP2:VP3 are 1 : 1 : 10.
• VPl, VP2, and VP3 interact together to form a capsid of an icosahedral symmetry.
• compositions for use in preventing or treating a disorder characterized by deficient autophagic flux (e.g, Danon disease) which comprises a therapeutically effective amount of a vector that comprises a nucleic acid sequence of a polynucleotide that encodes one or more isoforms of LAMP-2.
• a disorder characterized by deficient autophagic flux e.g, Danon disease
• a vector that comprises a nucleic acid sequence of a polynucleotide that encodes one or more isoforms of LAMP-2.
• the pharmaceutical compositions that contain the expression cassette or vector may be in any form that is suitable for the selected mode of administration, for example, for intraventricular, intramyocardial, intracoronary, intravenous, intra-arterial, intra-renal, intraurethral, epidural or intramuscular administration.
• the gene therapy vector comprising a polynucleotide encoding one or more LAMP-2 isoforms can be administered, as sole active agent, or in combination with other active agents, in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
• the pharmaceutical composition comprises cells transduced ex vivo with any of the gene therapy vectors of the disclosure.
• the pharmaceutical compositions contain vehicles (e.g, carriers, diluents and excipients) that are pharmaceutically acceptable for a formulation capable of being injected.
• vehicles e.g, carriers, diluents and excipients
• saline solutions monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts.
• Illustrative pharmaceutical forms suitable for injectable use include, e.g, sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the
• the disclosure provides methods of preventing, mitigating, ameliorating, reducing, inhibiting, eliminating and/or reversing one or more symptoms of Danon disease or another autophagy disorder in a subject in need thereof, comprising administering to the subject a gene therapy vector of the disclosure.
• Danon disease refers to an X-linked dominant skeletal and cardiac muscle disorder with
• the stem cells are capable of differentiation into muscle tissue, e.g ., cardiac muscle tissue and/or skeletal muscle tissue.
• the stem cells are autologous.
• the stem cells are induced pluripotent stem cells (iPSCs).
• the autophagy disorder is selected from the group consisting of end-stage heart failure, myocardial infarction, drug toxicities, diabetes, end-stage renal failure, and aging.
• the subject is a mammal, e.g. , a human.
• the subject is exhibiting symptoms of Danon disease or another autophagy disorder.
• the subject has been identified as having reduced or non- detectable LAMP-2 expression.
• the subject has been identified as having a mutated LAMP-2 gene.
• Subjects/patients amenable to treatment using the methods described herein include individuals at risk of a disease or disorder characterized by insufficient autophagic flux (e.g, Danon disease as well as other known disorders of autophagy including, but not limited to, systolic and diastolic heart failure, myocardial infarction, drug toxicities (for example, anthracyclines, chloroquine, and its derivatives), diabetes, end-stage renal disease, and aging) but not showing symptoms, as well as subjects presently showing symptoms.
• a disease or disorder characterized by insufficient autophagic flux e.g, Danon disease as well as other known disorders of autophagy including, but not limited to, systolic and diastolic heart failure, myocardial infarction, drug toxicities (for example, anthracyclines, chloroquine, and its derivatives), diabetes, end-stage renal disease, and aging) but not showing symptoms, as well as subjects presently showing symptoms.
• Such subject may have been
• the identity exists over a region that is at least about 25 amino acids or nucleotides in length, for example, over a region that is 50, 100, 200, 300, 400 amino acids or nucleotides in length, or over the full-length of a reference sequence.
• Administration can be by any route including parenteral and transmucosal (e.g, oral, nasal, vaginal, rectal, or transdermal).
• Parenteral administration includes, e.g, intravenous, intramuscular, intraarterial, intrarenal, intraurethral, intracardiac, intracoronary, intramyocardial, intradermal, epidural, subcutaneous, intraperitoneal, intraventricular, ionophoretic and intracranial.
• Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
• the effective amount is about lE+11 vg/kg to about 1E+12 vg/kg, about 1E+12 vg/kg to about 2E+12 vg/kg, about 2E+12 vg/kg to about 3E+12 vg/kg, about 3E+12 vg/kg to about 3E+13 vg/kg, or about 3E+13 vg/kg to about 3E+14 vg/kg of rAAV gene therapy vector. In some embodiments, the effective amount is about 3E+12 vg/kg to about 3E+14 vg/kg of rAAV gene therapy vector.
• the phrase“cause to be administered” refers to the actions taken by a medical professional (e.g ., a physician), or a person controlling medical care of a subject, that control and/or permit the administration of the agent(s)/compound(s) at issue to the subject.
• Causing to be administered can involve diagnosis and/or determination of an appropriate therapeutic or prophylactic regimen, and/or prescribing particular agent(s)/compounds for a subject.
• Such prescribing can include, for example, drafting a prescription form, annotating a medical record, and the like.
• the terms“treating” and“treatment” refer to delaying the onset of, retarding or reversing the progress of, reducing the severity of, or alleviating or preventing either the disease or condition to which the term applies, or one or more symptoms of such disease or condition.
• the terms“treating” and“treatment” also include preventing, mitigating, ameliorating, reducing, inhibiting, eliminating and/or reversing one or more symptoms of the disease or condition.
• vector is used herein to refer to a nucleic acid molecule capable transferring or transporting another nucleic acid molecule.
• the transferred nucleic acid is generally linked to, e.g. , inserted into, the vector nucleic acid molecule.
• a vector may include sequences that direct autonomous replication or reverse transcription in a cell, or may include sequences sufficient to allow integration into host cell DNA.
• “vectors” include gene therapy vectors.
• the term“gene therapy vector” refers to a vector capable of use in performing gene therapy, e.g. , delivering a polynucleotide sequence encoding a therapeutic polypeptide to a subject.
• the expression cassette can be comprised in a gene therapy vector.
• the term expression cassette excludes polynucleotide sequences 5’ to the 5’ ITR and 3’ to the 3’ ITR.
• EXAMPLE 2 DNA, RNA, and Protein Expression in Non-Human Primates Following Intravenous Administration of 1M O' 3 vg/kg AA V9.LAMP2B and AA Vrh 74.LAMP2B
• Non-human primate studies of AAV9 versus AAVrh74 vectors were performed in paired male and female African Green Monkeys (AGM). Subjects received either
• L AMP2B -H A-F 1 ag .“AAV9.LAMP2B-HA-Flag” is an AAV9 serotype adeno-associated virus vector encoding LAMP2B C-terminally fused to an HA-Flag tag.
• “AAVrh74.LAMP2B-HA-Flag” is an AAVrh74 serotype adeno-associated virus vector encoding LAMP2B C-terminally fused to an HA-Flag tag.
• One subject was given vehicle control.
• the vectors were administered by intravenous injection of 2 mL of 1.85 x 10 13 vector genomes (vg)/mL as determined by quantitative polymerase chain reaction (qPCR) using a plasmid containing the WPRE sequence to generate a reference curve.
• This injection achieved the target dose of vector, which was about 1.0 c 10 13 vg/kg. Due to lower body weight, female subjects received about 1.2 c 10 13 vg/kg of their respective vectors. This experiment is summarized in Table 2.
• DNA was extracted from frozen tissues using Qiagen DNeasy® kit. DNA purity (A260/A280) and concentration were evaluated on a NanoDrop OneTM spectrophotometer (Thermo). Quantitative PCR (qPCR) was performed on 20 ng DNA using TaqMan Universal Master Mix II (Thermo, 4440038) on a real-time PCR system (QuantStudio5, Thermo) using the following primers/probes:
• RNaseP housekeeping gene. Thermo
• Reverse primer 5 -GGGCCACAACTCCTCATAAA-3' (SEQ ID NO:34)
• FIG. 6A shows a micrograph of semi-quantitative mRNA analysis by RNAscope in an untreated left ventricle.
• FIG. 6B shows micrographs of semi-quantitative mRNA analysis by RNAscope in treated left ventricles.
• FIG. 7A shows a micrograph of semi-quantitative mRNA analysis by RNAscope in an untreated quadricep.
• FIG. 7B shows micrographs of semi-quantitative mRNA analysis by RNAscope in treated quadriceps.
• FIG. 8 shows micrographs of semi-quantitative mRNA analysis by RNAscope in treated gastrocnemius. Results are summarized for vehicle control (Table 3A), AAV9 (Table 3A), and AAVrh74 (Table 3C)
• the lysis buffer contains 300mM NaCl, 20mM EDTA, lOOmM Tris pH 8.0, 2% NP-40 and 0.2% SDS with CompleteTM EDTA-free protease inhibitor and PhosSTOPTM phosphatase inhibitor.
• Total protein was assessed by BCA (Thermo). 100 mg of total protein was loaded per well. A standard curve was constructed using purified human LAMP2 protein (Origene).
• ELISA was performed with a mouse monoclonal antibody (H4B4, Novus Biologicals) as the capture antibody, a goat polyclonal antibody (R&D Systems) as the detection antibody, HRP- linked antibody: Donkey anti-goat (Millipore) as the secondary antibody. Plates were developed with TMB (Thermo) and quantified on a spectrophotometer (Spectramax M5c).
• FIG. 9 shows a bar graph of protein quantification in tissues most affected in Danon disease by ELISA.
• FIG. 10A shows a bar graph of protein quantification in regions of the heart by ELISA.
• FIG. 10B shows a bar graph of protein quantification in muscles by ELISA.
• FIGS. 11A-11D show line graphs of clinical pathology measurement in NHP serum over course of study. Clinical pathology levels were assessed as changes in (FIG. 11 A) alanine aminotransferase, ALT; (FIG. 11B) aspartate aminotransferase, AST; (FIG. 11C) white blood cells, WBC; and (FIG. 11D) neutrophils over the study duration. B059 is the vehicle control. A991 and A602 are AAV9- treated animals. A710 and A981 are AAVrh74-treated animals. Conclusions
• AAVrh74 may be used as a vector to deliver LAMP2B to tissues relevant to treatment of Danon disease.
• AAVrh74 was non-inferior to AAV9 in these experiments.

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