446results about "Genetic material administration regime" patented technology

Disclosed herein are molecules and pharmaceutical compositions that induce an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion. Also described herein include methods for treating a disease or disorder that comprises a molecule or a pharmaceutical composition that induces an insertion, deletion, duplication, or alteration in an incorrectly spliced mRNA transcript to induce exon skipping or exon inclusion.

Provided herein are methods of inserting a nucleic acid encoding a polypeptide of interest into a target genomic locus in a cell or a population of cells in a subject, methods of expressing a polypeptide of interest from a target genomic locus in a cell or a population of cells in a subject, methods of treating an enzyme deficiency in a subject in need thereof, and methods of preventing or reducing the onset of a sign or symptom of an enzyme deficiency in a subject in need thereof. The methods use CD40 inhibitors (e.g., CD40 antigen-binding molecules) to mitigate immune response and facilitate redosing of nucleic acid constructs encoding a polypeptide of interest and nuclease agents targeting a target genomic locus to achieve, for example, a step-wise increase in expression of a polypeptide of interest in a subject following insertion of the nucleic acid construct without overshooting.

Provided herein are methods of inserting a nucleic acid encoding a polypeptide of interest into a target genomic locus in a cell or a population of cells in a subject, methods of expressing a polypeptide of interest from a target genomic locus in a cell or a population of cells in a subject, methods of treating an enzyme deficiency in a subject in need thereof, and methods of preventing or reducing the onset of a sign or symptom of an enzyme deficiency in a subject in need thereof. Some methods, such as when a subject has preexisting against an immunogen to be administered, use plasma cell depleting agents or combinations comprising plasma cell depleting agents to mitigate immune response and facilitate redosing of nucleic acid constructs encoding a polypeptide of interest and nuclease agents targeting a target genomic locus to achieve, for example, a step-wise increase in expression of a polypeptide of interest in a subject following insertion of the nucleic acid construct without overshooting. Other methods, such as when a subject has no preexisting immunity against an immunogen to be administered, use B cell depleting agents (e.g., anti-CD20xCD3 antibody or functional fragment thereof) to mitigate immune response and facilitate redosing of nucleic acid constructs encoding a polypeptide of interest and nuclease agents targeting a target genomic locus to achieve, for example, a step-wise increase in expression of a polypeptide of interest in a subject following insertion of the nucleic acid construct without overshooting.

Described herein are nucleic acid molecules, compositions, recombinant AAV (rAAV) particles, kits, and methods for delivering a base editor (or a "nucleobase editor") to a cell, for example via an AAV vector. In particular, the present disclosure provides compositions, methods and uses for delivery of adenine base editors and cytosine base editors in a single AAV vector (or genome). Further described herein are improved AAV vectors comprising a minimised size regulatory component, for example, a regulatory component that can enable packaging of a base editor. Provided herein are methods and compositions for delivering a base editor protein to a cell or tissue in a single recombinant AAV (rAAV) vector. Improved methods and compositions for in vivo delivery of these base editors in a single rAAV particle are contemplated herein. Further provided herein are base editors, and compositions and cells comprising these base editors.

The present disclosure provides recombinant adeno-associated virus (rAAV) vectors, methods of treating ocular conditions, pharmaceutical compositions, and other compositions and methods, wherein the rAAV vectors comprise a polynucleotide encoding an oxidoreductase. Methods of treatment may include administration to the lacrimal gland.

Disclosed herein are nucleic acid compositions and methods of use. The nucleic acid compositions may have a therapeutic nucleic acid sequence operably linked to a nuclear targeting sequence that increases expression of the therapeutic nucleic acid in a cell by at least 1.25 fold; at least 80% sequence identity to SEQ ID NO: 6; or a first regulatory element comprising a promoter sequence operably linked to a hemoglobin subunit gamma intron (hBGi) sequence, and a second regulatory element comprising a woodchuck hepatitis posttranscriptional regulatory element (WPRE) sequence. The nucleic acid compositions with these features may enhance therapeutic nucleic acid transfection and expression. Also disclosed herein are transgenes optimized for gene therapy applications, including novel FVIII transgene sequences, in which the B domain may be non-naturally occurring the A1 and / or A3 domain may include at least one amino acid substitution.

The invention belongs to the field of preparation of biomedical nano-materials, and particularly relates to a tumor microenvironment responsive bacterium-nano hybrid system as well as a preparation method and application thereof. According to the invention, an engineering bacterium containing an acid response promoter and coding PD-L1 blocking peptide is prepared, and then lipidosome nanoparticles containing calcium carbonate, curcumin and an XIAP / cIAP1 antagonist are attached to the bacterium, so that the bacterium-nano hybrid system with tumor microenvironment response is obtained. The system can realize accurate drug delivery and controllable release in an acidic tumor microenvironment through a unique pH response mechanism, shows remarkable tumor targeting and treatment effects, and can be used as an anti-tumor drug.

A dual vector system for treating ornithine transcarbamylase deficiency is provided. The system includes ((a) a gene editing AAV comprising a first AAV rh79 capsid and a first vector genome comprising a 5′ ITR, a sequence encoding a meganuclease that targets PCSK9 under control of regulatory sequences that direct expression of the meganuclease in a target cell comprising a PCSK9 gene, and a 3′ ITR; and(b) a donor AAV vector comprising a second AAV capsid and a second AAV rh79 vector genome comprising: a 5′ITR, a 5′ homology directed recombination (HDR) arm, a transgene encoding ornithine transcarbamylase (OTC) and regulatory sequences that direct expression of the transgene in the target cell, a 3′ HDR arm, and a 3′ ITR.

To provide a pharmaceutical composition comprising the recombinant nucleic acid, and to provide a method of treating Leber's hereditary optic neuropathy (LHON) using the pharmaceutical composition.SOLUTION: Provided is a pharmaceutical composition for use in combination with a second pharmaceutical composition to treat Leber's hereditary optic neuropathy (LHON) in a patient in need thereof, the pharmaceutical composition comprising a nucleic acid sequence encoding a mitochondrial-tropic peptide and comprising a therapeutically effective amount of an adeno-associated virus (AAV) comprising a recombinant nucleic acid to which a promoter is operably linked, the second pharmaceutical composition comprising a steroid, the steroid being methylprednisolone or prednisone, the steroid being administered daily for two days prior to the administration of the pharmaceutical composition.SELECTED DRAWING: Figure 8

Provided herein is a method for improving delivery of a pharmaceutical composition to the central nervous system in a subject in need thereof, the method comprising administering to the subject, in combination with the pharmaceutical composition, an agent that enhances glymphatic influx.

To provide compositions and methods for regulating protein production in target cells. [Solution] The compositions and methods disclosed herein can improve diseases associated with protein or enzyme deficiency. The present invention provides, for example, a composition comprising (a) at least one mRNA molecule that is at least partly encoding a functionally secreted polypeptide, and (b) a transport vehicle comprising lipid nanoparticles. The present invention also provides a method for treating a subject deficient in a functional polypeptide, comprising administering a composition comprising (a) at least one mRNA that is at least partly encoding the functionally secreted polypeptide, and (b) a transport vehicle comprising lipid nanoparticles, wherein after administration of the composition, the mRNA is expressed in a target cell to produce the functionally secreted polypeptide.

To provide a gene therapy for treating mucopolysaccharidosis type I.SOLUTION: Provided is a treatment regimen useful for the treatment of α-L-iduronidase deficiency in human patients, the regimen comprising administering to the patient: (a) a recombinant AAV having a nucleic acid, comprising an AAV9 capsid and a sequence encoding human α-L-iduronidase under the control of regulatory sequences that direct its expression in the patient; (b) a first immunosuppressant selected from glucocorticoids, steroids, antimetabolites, T-cell inhibitors, macrolides, or cytostatics; and (c) a second immunosuppressant selected from glucocorticoids, steroids, antimetabolites, T-cell inhibitors, macrolides, or cytostatics.SELECTED DRAWING: Figure 22

The disclosure relates to methods of delivering a gene therapy agent to a subject, treating an individual in need of a gene therapy agent, increasing expression of a gene therapy agent, reducing an immune response to a gene therapy agent, and preventing immune-related adverse events in a subject by administering a gene therapy agent and an IL-2 conjugate to the subject. The IL-2 conjugate has at least one amino acid residue replaced by an unnatural amino acid linked to a conjugating moiety. The disclosure further relates to methods of selecting a subject for treatment with a gene therapy agent and an IL-2 conjugate.

The present invention provides a mutant of adeno-associated virus serotype 1 (AAV1) capsid protein, a nucleic acid encoding the mutant of the AAV1 capsid protein, a recombinant AAV1 vector carrying the nucleic acid encoding the mutant of AA1 capsid protein, and a pharmaceutical composition containing the vector, wherein the mutant has a specific amino acid substituted at a certain position, compared to the amino acid sequence of the wild type AAV capsid protein. Specifically, the recombinant virus vector carrying the nucleic acid encoding the mutant of the AAV1 capsid protein enhances the expression of introduced genes in the pulmonary bronchi when delivered in an aerosol state through the bronchi, making it useful for the prevention or treatment of diseases related to the pulmonary bronchi.

Nanoparticles comprising a nucleic acid molecule encoding human ubiquitin-like protein 5 (UBL5) or human UBL5 protein are provided. Methods of treating a disease, disorder or condition characterized by mitochondrial stress are provided. Expression vectors, nucleic acid molecules, peptides, pharmaceutical compositions and methods of identifying a gene for use in gene therapy, targeting an agent to a CD44 expressing cell and producing a therapeutic nanoparticle are also provided.

Provided herein is a gene therapy for JPH2 (junctophilin-2), for example, using an adeno-associated virus (AAV) vector. The promoter of the vector can be the MHCK7 promoter or the cardiac troponin T (HTNNT2) promoter. The capsid can be the AAV9 or AAVrh74 capsid or a functional variant thereof. Other promoters or capsids may be used. Further provided are methods of treatment, such as by intravenous, intracoronary, intracarotid or intracardiac administration of rAAV vectors, as well as other compositions and methods. TIFF2024546103000093.tif151154

Provided herein are methods and compositions for treating cancer in an individual comprising administering to the individual an effective amount of at least one CD122 / CD132 agonist, at least one immune checkpoint inhibitor and a viral composition comprising one or more viruses engineered to overexpress a tumor suppressor gene and / or an adenoviral death protein. Also provided herein are methods and compositions for treating cancer in an individual comprising administering to the individual an effective amount of at least one oncolytic viral composition and at least one CD122 / CD132 agonist and at least one immune checkpoint inhibitor. Also provided herein are methods of enhancing anti-tumor efficacy by administering the agents described above in combination with other cancer therapies. In highly aggressive forms of cancer, known to be generally resistant to immune therapies, these treatments unexpectedly resulted in complete tumor remissions and curative outcomes.

The present invention relates to the field of therapy. More in particular, the invention relates to therapeutic methods wherein an effector component is administered that requires cellular uptake to become effective and / or that exerts its effect via an intracellular (molecular) target, such as, but not limited to, nucleic acid or oligonucleotide therapeutics. The present invention provides modalities to extend the duration of effect of the effector component and / or extend the dosing interval of the effector component and / or reduce the dosing frequency of the effector component and / or to cause a (delayed) boost of the effect of the effector component.

AAV vectors are ideally suited for long-term delivery of a combination of broadly neutralizing antibodies to achieve sterilizing immunity to HIV. Unfortunately, host immune responses to the delivered antibody have severely limited the efficacy. The TLR9 pathway has been identified in initiating adaptive immune responses against AAV and delivered bNAbs. To enhance this strategy, we validated Hydroxychloroquine, a known drug inhibitor of the TLR9 pathway, as a pretreatment to AAV delivery to avoid anti-drug antibody responses. TLR9 signaling inhibition was validated using a HEK-Blue hTLR9 reporter cell line and CpG stimulation. Hydroxychloroquine was also validated in a 3-macaque trial where AAV9-3BNC117 and AAV9-10-1074 were administered along with 3 doses of hydroxychloroquine once a week starting 1 week before AAV inoculation. Unlike historical controls, where 3BNC117 and 10-1074 expression is lost within the first 4-5 weeks, 2 macaques maintained 10-1074 expression and 1 macaque maintained 3BNC117 for the duration of the trial. Anti-3BNC117 antibodies were only observed in 2 of the 3 macaques and were significantly delayed. Anti-10-1074 antibody responses were a log lower than typically observed in historic controls. The use of hydroxychloroquine as a pretreatment for AAV inoculation is a promising strategy. The significant decrease in anti-10-1074 antibody levels and the successful delivery of 10-1074 in 2 macaques and 3BNC117 in 1 macaque was very encouraging. Extending the dosage of hydroxychloroquine beyond 3 doses may be sufficient to observe long-term bNAb expression in all animals and further decrease ADA responses. Together, these data suggest that the short-term treatment of hydroxychloroquine at the time of AAV inoculation has a meaningful impact on tolerance induction to our AAV-delivered bNAbs.

The invention relates to a method or regimen comprising the administration of IgG cysteine protease to a subject in order to improve the benefit of a subsequent vector-based therapy, where the vector-based therapy treats a disease or condition in said subject. Accordingly, the invention also relates to the treatment of diseases or conditions with a vector-based therapy. The method comprises administering to the subject at least two doses of an IgG cysteine protease; and subsequently administering said vector-based therapy. Methods of the invention are particularly useful for subjects who have pre-existing immunity or pre-existing neutralizing antibodies against the vector-based therapy.

The present invention relates to means and method for AAV based gene therapies in humans. In particular, the present invention relates to the treatment of human patients that may be suspected to have antibodies directed against the AAV intended for use in said treatment.

The present invention relates generally to the field of molecular biology. In particular, the specification teaches methods of preventing or treating an RNA viral infection in a subject.

Methods and compositions for the treatment of cognitive disorders are provided herein.The present disclosure generally relates to the field of methods for delivering gene therapy to the entorhinal / hippocampal region accurately and safely to treat cognitive disorders and other diseases of the central nervous system (CNS).The present disclosure describes the specific parameters for targeting this network of brain regions, including accurate anatomical target, vector concentration and vector volume, and the subject may be at risk of suffering from a condition selected from Alzheimer's disease (AD), mild cognitive impairment, pre-symptomatic AD, frontotemporal dementia, or Lewy body dementia.

Disclosed herein is a method for the treatment of Pompe disease, comprising administering a recombinant AAV (rAAV) vector comprising a rAAV genome comprising a heterologous nucleic acid encoding an acid alpha-glucosidase (GAA) polypeptide operably linked to a liver-specific promoter, wherein the subject has been discontinued or is not receiving enzyme replacement therapy (ERT).The technology described herein generally relates to gene therapy constructs, methods and compositions for the treatment of Pompe disease.

Provided herein are methods and compositions for plakophilin-2 gene therapy for treating heart diseases such as arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy (ACM).

The present invention relates to methods for treating diseases by the in vivo gene editing of hematopoietic stem and progenitor cells (HSPCs), and in particular to the use of a CXCR4 antagonist to increase the efficiency of HSPC gene editing in vivo when administered prior to or in conjunction with administration of a gene editing system to a subject in need thereof.

The present disclosure relates to chimeric adeno-associated virus capsids and related adeno-associated viruses targeting glial progenitor cells.

Methods and compositions for retinal gene therapy are described herein. In one aspect, a method of treating a patient in need thereof is described. In some embodiments, the method comprises performing a vitrectomy on the eye of the patient, and delivering a payload, such as a gene therapy vector, to the retina of the eye of the patient. In some instances, the method further comprises removing the inner limiting membrane (ILM) of the eye of the patient before delivering the payload to the retina of the eye of the patient. In one aspect, compositions for retinal gene therapy are described. In such embodiments, a composition comprises a payload and an adjuvant.

Provided are recombinant adeno-associated virus (rAAV) vectors, methods of treating an ocular condition, pharmaceutical compositions, and other compositions and methods, in which the rAAV vector comprises a polynucleotide encoding oxidoreductase enzymes. Methods of treatment may include administration to the lacrimal gland.