Modulators of adeno-associated virus transduction and uses thereof
AssigneeNovartis AG
InventorsEloise Hudry, Katie Kubek-Luck, Keith Mansfield
Life of this patent
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Abstract
The disclosure provides compositions and methods for modulating transduction efficiency of AAV particles. Specifically, the disclosure provides AAV transduction modulators that modulate genes or gene products associated with AAV transduction efficiency in gene therapies.
Claims236
A method of modulating transduction efficiency of an AAV particle, comprising:
- contacting a cell with an AAV transduction modulator,
- thereby modulating the transduction efficiency of the AAV particle.
The method of claim 2, wherein the modulator modulates (e.g., increases or decreases) a gene or gene product associated with AAV transduction efficiency.
The method of claim 2 or 3, wherein the gene or gene product is a mammalian (e.g., human) gene or gene product.
The method of any of the preceding claims, wherein the modulator inhibits the gene or gene product, e.g., a gene or gene product that is associated with a decreased transduction efficiency of an AAV particle.
The method of any of the preceding claims, wherein the modulator activates the gene or gene product, e.g., a gene or gene product that is associated with an increased transduction efficiency of an AAV particle.
The method of any of the preceding claims, wherein the gene or gene product is associated with an increased transduction efficiency of an AAV particle (e.g., AAV-R or GPR108).
The method of any of the preceding claims, wherein the gene or gene product is associated with an increased transduction efficiency of an AAV particle of a first serotype (e.g., AAV2) and an increased transduction efficiency of an AAV particle of a second serotype (e.g., AAV9) (e.g., AAV-R or GPR108).
The method of any of the preceding claims, wherein the gene or gene product is associated with a decreased transduction efficiency of an AAV particle (e.g., WDR11 or MRE11).
The method of any of the preceding claims, wherein the gene or gene product is associated with a decreased transduction efficiency of an AAV particle of a first serotype (e.g., AAV2) and a decreased transduction efficiency of an AAV particle of a second serotype (e.g., AAV9) (e.g., WDR11 or MRE11).
The method of any of the preceding claims, wherein the gene or gene product, when modulated, increases the transduction efficiency of an AAV particle.
The method of any of the preceding claims, wherein the gene or gene product, when modulated, increases the transduction efficiency of an AAV particle of a first serotype (e.g., AAV2) and the transduction efficiency of an AAV particle of a second serotype (e.g., AAV9).
The method of any of the preceding claims, wherein the gene or gene product, when modulated, decreases the transduction efficiency of an AAV particle.
The method of any of the preceding claims, wherein the gene or gene product, when modulated, decreases the transduction efficiency of an AAV particle of a first serotype (e.g., AAV2) and the transduction efficiency of an AAV particle of a second serotype (e.g., AAV9).
The method of any of the preceding claims, wherein the gene product is an RNA.
The method of any of the preceding claims, wherein the gene product is a protein.
The method of any of the preceding claims, wherein the gene or gene product is preferentially expressed in a target tissue (e.g., brain or liver).
The method of any of the preceding claims, wherein the modulator alters (e.g., increases or decreases) the expression of the gene.
The method of any of the preceding claims, wherein the modulator alters the structure of the gene.
The method of any of the preceding claims, wherein the modulator alters (e.g., increases or decreases) an activity (e.g., an enzymatic activity) of the gene product.
The method of any of the preceding claims, wherein the modulator alters (e.g., increases or decreases) the level (e.g., abundance) of the gene product.
The method of any of the preceding claims, wherein the modulator alters (e.g., increases or decreases) the stability of the gene product.
The method of any of the preceding claims, wherein the modulator alters (e.g., increases or decreases) transduction efficiency of an AAV particle, e.g., as determined by an assay described herein.
The method of any of the preceding claims, wherein the modulator increases transduction efficiency of an AAV particle,
- optionally wherein the modulator increases transduction to at least 10, 20, 30, 40, 50, or 60 viral copies per genome,
- optionally wherein the modulator increases transduction to at least 103, 104, 105, 106, or 107 viral copies per μg DNA.
The method of any of the preceding claims, wherein the transduction efficiency is increased by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000-fold, compared to a reference level of transduction efficiency.
The method of any of the preceding claims, wherein the modulator decreases transduction efficiency of an AAV particle,
- optionally wherein the modulator decreases transduction to no more than 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 viral copies per genome,
- optionally wherein the modulator decreases transduction to no more than 102, 103, or 104 viral copies per μg DNA.
The method of any of the preceding claims, wherein the transduction efficiency is decreased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 750/, 80/, 85/, 90%, 95%, 96%, 97%, 98%, 99%, or 100%, compared to a reference level of transduction efficiency.
The method of any of the preceding claims, wherein the reference level of transduction efficiency is the level of transduction efficiency in a cell that has not been contacted with the AAV transduction modulator.
The method of any of the preceding claims, wherein the reference level of transduction efficiency is the level of transduction efficiency before the cell is contacted with the AAV transduction modulator.
The method of any of the preceding claims, wherein the gene or gene product increases the transduction efficiency of an AAV2 particle,
- optionally wherein the gene or gene product does not increase, or does not substantially increase, the transduction efficiency of an AAV9 particle,
- optionally wherein the gene or gene product is AAV-R or GRP108.
The method of any of the preceding claims, wherein the modulator is:
- (a) a gene editing system targeted to one or more sites within the gene or a regulatory element thereof;
- (b) a nucleic acid encoding one or more components of the gene editing system;
- or
- (c) a combination thereof.
The method of any of the preceding claims, wherein the AAV particle comprises an AAV genome.
The method of any of the preceding claims, wherein the AAV particle comprises an AAV-like particle.
The method of any of the preceding claims, wherein the AAV particle comprises a capsid.
The method of any of the preceding claims, wherein the AAV particle has a serotype of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, or a combination thereof.
The method of any of the preceding claims, wherein the AAV particle is an AAV2 particle.
The method of any of the preceding claims, wherein the AAV particle is an AAV9 particle.
The method of any of the preceding claims, wherein the AAV particle has a tropism towards the CNS (e.g., AAV1, AAV2, AAV4, AAV5, AAV8, or AAV9).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards heart (e.g., AAV1, AAV8, or AAV9).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards kidney (e.g., AAV2).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards liver (e.g., AAV7, AAV8, or AAV9).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards lung (e.g., AAV4, AAV5, AAV6, or AAV9).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards pancreas (e.g., AAV8).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards a photoreceptor cell (e.g., AAV2, AAV5, or AAV8).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards retinal pigment epithelium (RPE) (e.g., AAV1, AAV2, AAV4, AAV5, or AAV8).
The method of any of the preceding claims, wherein the AAV particle has a tropism towards skeletal muscle (e.g., AAV1, AAV6, AAV7, AAV8, or AAV9).
The method of any of the preceding claims, wherein the AAV particle comprises a nucleotide sequence encoding a therapeutic protein, e.g., a protein associated with a disorder described herein.
The method of any of the preceding claims, wherein the AAV particle comprises a nucleotide sequence encoding NGF, APOE2 (e.g., hAPOE2), TERT (e.g., hTERT), MAPT, GAD, AADC, NTN, GDNF, GCase, HIT, SMN, SMN2, SOD1, or C9orf72.
The method of any of the preceding claims, wherein the AAV particle comprises a nucleotide sequence encoding a therapeutic nucleic acid, e.g., a nucleic acid targeting a nucleotide sequence encoding a protein associated with a disorder described herein.
The method of any of the preceding claims, wherein the cell is a brain cell, a liver cell, a spinal cord cell, a dorsal root ganglion (DRG) cell, a spleen cell, a lymph node cell, a kidney cell, a lung cell, a heart cell, a muscle cell (e.g., a skeletal muscle cell, e.g., a femur muscle cell), a diaphragm cell, a bone marrow cell, or a gonad cell.
The method of any of the preceding claims, wherein the cell is a central nervous system (CNS) cell.
The method of any of the preceding claims, wherein the cell is a brain cell.
The method of any of the preceding claims, wherein the cell is a DRG cell.
The method of any of the preceding claims, wherein the cell is a liver cell;
- optionally wherein the modulator increases transduction to at least 10, 20, 30, 40, 50, or 60 viral copies per liver cell genome,
- optionally wherein the modulator increases transduction to at least 105, 106, or 107 viral copies per μg DNA in the liver cell.
The method of any of the preceding claims, wherein the cell is contacted with the AAV transduction modulator in vitro.
The method of any of the preceding claims, wherein the cell is contacted with the AAV transduction modulator ex vivo.
The method of any of the preceding claims, wherein the cell is contacted with the AAV transduction modulator in vivo, optionally wherein the method results in a high gene modulating (e.g., gene editing) efficiency (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%) in a first tissue (e.g., liver), with limited impact (e.g., a gene modulating (e.g., gene editing) efficiency of 20%, 15%, 10%, 5%, 2%, or less) in a second tissue (e.g., skeletal muscle, bone marrow, or both).
A method of modulating transduction efficiency of an AAV particle, the method comprising:
- administering to a subject in need thereof an effective amount of an AAV transduction modulator,
- thereby modulating the transduction efficiency of the AAV particle.
A method of treating a disorder, the method comprising:
- administering to a subject in need thereof an effective amount of a therapy comprising an AAV genome or an AAV particle, wherein a gene or gene product associated with AAV transduction efficiency is modulated in the subject,
- thereby treating the disorder.
A method of treating a disorder, the method comprising:
- administering to a subject in need thereof an effective amount of (a) an AAV transduction modulator and (b) a therapy comprising an AAV genome or an AAV particle,
- thereby treating the disorder.
A method of preparing a subject for a therapy comprising an AAV genome or an AAV particle, the method comprising:
- administering to the subject an effective amount of an AAV transduction modulator,
- thereby preparing the subject for the therapy.
A method of reducing the toxicity of a therapy comprising an AAV genome or an AAV particle, the method comprising:
- administering to a subject in need thereof an effective amount of an AAV transduction modulator;
- thereby reducing the toxicity of the therapy.
A method of enhancing the efficacy of a therapy comprising an AAV genome or an AAV particle, the method comprising:
- administering to a subject in need thereof an effective amount of an AAV transduction modulator,
- thereby enhancing the efficacy of the therapy.
A method of producing a cell having an increased AAV transduction efficiency, comprising:
- contacting a cell with an AAV transduction modulator,
- thereby producing the cell.
A cell comprising an AAV modulator described herein and an AAV particle.
A pharmaceutical composition comprising an AAV modulator described herein and an AAV particle.
A kit comprising an AAV modulator described herein and an AAV particle.
An AAV transduction modulator (e.g., as described herein) for use in a method of modulating transduction efficiency of an AAV particle in a cell or a subject.
An AAV transduction modulator (e.g., as described herein) for use in combination with an AAV genome or an AAV particle in a method of treating a disorder in a subject.
An AAV transduction modulator (e.g., as described herein) for use in a method of preparing a subject for a therapy comprising an AAV genome or an AAV particle.
An AAV transduction modulator (e.g., as described herein) for use in a method of reducing the toxicity of a therapy comprising an AAV genome or an AAV particle in a subject.
An AAV transduction modulator (e.g., as described herein) for use in a method of increasing the efficacy of a therapy comprising an AAV genome or an AAV particle in a subject.
Use of an AAV transduction modulator (e.g., as described herein) in the manufacture of a medicament for modulating transduction efficiency of an AAV particle in a cell or a subject.
Use of an AAV transduction modulator (e.g., as described herein) in the manufacture of a medicament in combination with an AAV genome or an AAV particle for treating a disorder in a subject.
Use of an AAV transduction modulator (e.g., as described herein) in the manufacture of a medicament for preparing a subject for a therapy comprising an AAV genome or an AAV particle.
Use of an AAV transduction modulator (e.g., as described herein) in the manufacture of a medicament for reducing the toxicity of a therapy comprising an AAV genome or an AAV particle in a subject.
Use of an AAV transduction modulator (e.g., as described herein) in the manufacture of a medicament for increasing the efficacy of a therapy comprising an AAV genome or an AAV particle in a subject.
Dependencies are inferred from the claim text.