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AssigneeTrustees of Dartmouth College
InventorsCharles SENTMAN, David GRABER, W. James COOK
Estimating the term…
The present disclosure generally relates to novel chimeric antigen receptors (“CARs”), modified regulatory T cells (“Tregs”) expressing such CARs and/or Tregs which are engineered to express neurodegenerative disease modifying molecules, e.g., which express molecules which prevent oxidative/inflammatory activity, or which promote neuronal growth/survival such as nerve growth factors or non-classical neurotrophic factors. The present disclosure also generally relates to compositions containing such modified Tregs, and methods of use thereof as therapeutics, in particular for treating and preventing neurodegenerative diseases and symptoms associated with therewith, and/or for slowing the onset of such neurodegenerative diseases, particularly in persons at risk because of genetic factors or in persons exhibiting early signs of developing such a neurodegenerative disease.
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) which targets at least one (i) aberrant protein which is expressed at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (e.g. overexpressed) at site(s) of neurodegeneration associated with a specific neurodegenerative disease and/or is associated with the pathology of said specific neurodegenerative disease or condition, or in addition the cells are engineered to express a neurodegenerative disease modifying molecule (NDMM), wherein said CAR and NDMM may be expressed by the same or different cells, wherein said CAR and/or NDMM expressing cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is associated with the expression of said aberrant or aberrantly expressed protein.
The method of any of the foregoing claims, wherein said CAR-expressing cells comprise immune cells.
The method of any of the foregoing claims, wherein the administered cells comprise a CAR which recognizes at least one aberrant protein expressed at a site of neurodegeneration.
The method of any of the foregoing claims, wherein the CAR comprises an scFv or ligand which recognizes at least one aberrant protein or aberrantly expressed protein expressed at a site of neurodegeneration.
The method of any one of the foregoing claims, wherein the CAR comprised on said administered cells comprises DG01 (SEQ ID NO:
The method of any one of the foregoing claims, wherein said administered cells are engineered to express one or more of the following constructs:
The method of any one of the foregoing claims, wherein said administered cells are engineered to express one or more of the following:
The method of any of the foregoing claims, wherein said CAR cells are further engineered to express at least one NDMM, e.g., a pro-neuronal factor or nerve growth factor, wherein said CAR and said NDMM are expressed by the same or different cells.
The method of any one of the foregoing claims, wherein said administered cells are engineered to express NDMM Nrf2 (Keap1 inhibitor peptide) (SEQ ID NO:
The method of any one of the foregoing claims, wherein said administered cells are engineered to express human catalase (SEQ ID NO:
The method of any one of the foregoing claims, wherein said administered cells are engineered to express BDNF (SEQ ID NO:
The method of any one of the foregoing claims, wherein said administered cells are engineered to express IGF-1 (SEQ ID NO:
The method of any of the foregoing claims, wherein said cells are further engineered to express at least one anti-oxidative protein which inhibits or protects neurons from anti-oxidative stress and/or inhibits or prevents the death of neurons at the site of neurodegeneration, wherein said CAR and said anti-oxidative protein are expressed by the same or different cells.
The method of any of the foregoing claims, wherein the neurodegenerative disease or condition comprises at least one of Parkinson's disease, Alzheimer's disease, Prion disease, a Motor neurone disease (MND) such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA), Priedreich's ataxia, Lewy body disease, epilepsy, encephalitis, hydrocephalus, stroke, chronic traumatic encephalopathy (CTE);
The method of any of the foregoing claims, wherein the neurodegenerative disease comprises Parkinson's disease.
The method of any of the foregoing claims, wherein the neurodegenerative disease comprises Alzheimer's disease.
The method of any of the foregoing claims, wherein the neurodegenerative disease comprises amyotrophic lateral sclerosis (ALS).
The method of any of the foregoing claims, wherein the CAR binds to one or more of human amyloid beta, amyloid-beta 1-42, alpha-synuclein, superoxide dismutase-1 (SOD-1), hyperphosphorylated tau protein;
The method of any of the foregoing claims, wherein the administered cells express at least one pro-neuronal factor, neurotrophic factor, or nerve growth factor selected from brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF), interleukin-1 receptor antagonist (IL-1ra);
The method of any of the foregoing claims, wherein the administered cells express at least one anti-oxidative protein selected from superoxide dismutases such as human superoxide dismutase, Cu/Zn superoxide dismutase, HO-1, ferritin, glutathione reductase, glutathione peroxidase, ferritin (H), metallothionein I, thioredoxin, thioredoxin reductase, peroxiredoxins (Prxs) such as pereoxiredoxin MSP23;
The method of any of the foregoing claims, wherein the administered cells reduce or stabilize the amount of inflammation present at said site(s) of neurodegeneration.
The method of any of the foregoing claims, wherein the administered cells inhibit or prevent at least one of:
The method of any of the foregoing claims, wherein the administered cells slow the onset of the neurodegenerative disease.
The method of any of the foregoing claims, wherein the administered cells slow the progression of the neurodegenerative disease.
The method of any of the foregoing claims, wherein the administered cells repair or increase neural cell function or slow the loss of neural cell function.
The method of any of the foregoing claims, wherein the administered cells increase cognition or stabilize the loss of cognition in the treated subject.
The method of any of the foregoing claims, wherein the administered cells reduce or slow the loss of neuromotor function and/or paralysis in the treated subject.
The method of any of the foregoing claims, wherein the administered cells reduce the number or size of neural lesions or plaques in the treated subject.
The method of any of the foregoing claims, wherein the administered cells reduce the number of or severity of seizures in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells express increased levels of IL-10 in response to mSOD1 antigen in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells express increased levels of cell surface markers including one or more of GITR, PD-1 and/or CTLA-4 in response to mSOD1 antigen in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells inhibit superoxide generation in response to mSOD1 antigen and/or anti-CD3 in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells inhibit TNF-α production in response to mSOD1 antigen in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells express increased levels of IL-10 and/or IL-4 in response to amyloid beta antigen in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells inhibit superoxide generation in response to amyloid beta antigen and/or anti-CD3 in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells inhibit IL-6 production in response to amyloid beta antigen and/or anti-CD3 in the treated subject.
The method of any one of the foregoing claims, wherein the administered cells protect cells of the treated subject from hydrogen peroxide toxicity.
The method of any one of the foregoing claims, wherein the administered cells protect cells of the treated subject from hydrogen peroxide toxicity.
The method of any of the foregoing claims, wherein the cells are administered systemically or locally.
The method of any of the foregoing claims, wherein the cells cross the blood brain barrier (BBB).
The method of any of the foregoing claims, wherein the cells are administered by injection, e.g. by a means selected from intravenous, subcutaneous, intracavitary, intraventricular, intracranial, and intrathecal.
The method of any of the foregoing claims, wherein the CAR comprises an scFv which binds to one or more of human amyloid beta, human superoxide dismutases, or human alpha-synuclein.
The method of any of the foregoing claims, wherein the CAR comprises an scFv which binds to one or more of human amyloid beta, human superoxide dismutases, or human alpha-synuclein having a sequence contained in Table 1.
The method of any of the foregoing claims, wherein the administered cells further comprise a suicide gene, optionally expressed under the control of an inducible promoter.
The method of any of the foregoing claims, wherein the CAR expressed by the administered cells comprises at least one signaling domain, e.g., a costimulatory domain, optionally selected from CD28-CD3ζ, 4-1BB-CD3ζ, DAP10-CD3ζ, CD44-CD3ζ, CTLA4-CD3ζ, CD28, DAP10, 4-1BB and CD3ζ.
The method of any of the foregoing claims, wherein the CAR expressed by the administered cells comprises at least one signaling domain selected from CD28-CD3ζ, DAP10-CD3ζ, CD44-CD3ζ, CD28 and CD3ζ.
The method of any of the foregoing claims, wherein the cells express several CARs which recognize different proteins expressed at sites of neurodegeneration or the administered cells are comprise of cells which themselves express different CARs according to any of the foregoing claims.
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory domain, the expression of which are optionally controlled by the same or different inducible or constitutive promoters.
The nucleic acid of any of the foregoing claims, which further encodes human catalase and/or the Neh2 domain of human Nrf2.
The nucleic acid of any of the foregoing claims, which further encodes human IGF-1.
The nucleic acid of any of the foregoing claims, which further encodes human BDNF.
The nucleic acid of any one of the foregoing claims, which further encodes one or more of the following constructs:
The nucleic acid of any of the foregoing claims, wherein a ligand binding domain in the CAR comprises a scFv.
The nucleic acid of any of the foregoing claims, wherein the CAR comprises at least one signaling domain e.g., a costimulatory domain, optionally selected from CD28-CD3ζ, 4-1BB-CD3ζ, DAP10-CD3ζ, CD44-CD3ζ, CTLA4-CD3ζ, CD28, DAP10, 4-1BB and CD3ζ.
The nucleic acid of any of the foregoing claims, which encodes one or more of the following:
The nucleic acid of any of the foregoing claims, which encodes one or more of the following:
The nucleic acid of any of the foregoing claims, which encodes one or more of the following:
The nucleic acid of any of the foregoing claims, which is contained on a construct such as a plasmid or a virus, e.g., a retroviral construct.
The nucleic acid of any of the foregoing claims, wherein the nucleic acid encoding the CAR is contained on a construct which further comprises a gene encoding a pro-neuronal factor and/or an anti-oxidant protein and/or a nerve growth factor or non classical neurotrophic factor.
The nucleic acid of any of the foregoing claims, wherein the nucleic acid encoding the CAR is contained on a construct which further comprises a nucleic acid encoding at least one anti-oxidative protein, e.g., one which prolongs T cell function and/or which is neuroprotective.
The nucleic acid of any of the foregoing claims, wherein the ligand binding moiety in the CAR binds to an aberrant protein or a protein which is aberrantly expressed at sites of neurodegeneration or neuroinflammation present in individuals comprising a neurodegenerative disease or condition selected from Parkinson's disease, Alzheimer's disease, Prion disease, a Motor neurone disease (MND) such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body disease, epilepsy, encephalitis, hydrocephalus, stroke, chronic traumatic encephalopathy (CTE);
The nucleic acid of any of the foregoing claims, wherein the ligand binding moiety in the CAR binds to an aberrant protein or a protein which is aberrantly expressed at sites of neurodegeneration or neuroinflammation present in individuals comprising Parkinson's disease.
The nucleic acid of any of the foregoing claims, wherein the ligand binding moiety in the CAR binds to an aberrant protein or a protein which is aberrantly expressed at sites of neurodegeneration or neuroinflammation present in individuals comprising Alzheimer's disease.
The nucleic acid of any of the foregoing claims, wherein the ligand binding moiety in the CAR binds to an aberrant protein or a protein which is aberrantly expressed at sites of neurodegeneration or neuroinflammation present in individuals comprising amyotrophic lateral sclerosis (ALS).
The nucleic acid of any of the foregoing claims, wherein a ligand binding moiety in the CAR binds to one or more of human amyloid beta, amyloid-beta 1-42, alpha-synuclein, superoxide dismutase-1 (SOD-1), hyperphosphorylated tau protein;
The nucleic acid of any of the foregoing claims, which comprises a nucleic acid encoding at least one pro-neuronal factor, neurotrophic factor, or nerve growth factor selected from brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell-line derived neurotrophic factor (GDNF), interleukin-1 receptor antagonist (IL-1 ra);
The nucleic acid of any of the foregoing claims, which comprises a nucleic acid encoding an anti-oxidative protein which is selected from superoxide dismutases such as human superoxide dismutase, Cu/Zn superoxide dismutase, HO-1, ferritin, glutathione reductase, glutathione peroxidase, ferritin (H), metallothionein I, thioredoxin, thioredoxin reductase, peroxiredoxins (Prxs) such as pereoxiredoxin MSP23;
A recombinant or engineered cell which comprises at least one nucleic acid encoding a CAR according to any of the foregoing cells.
A recombinant or engineered cell according to any of the foregoing claims which does not express a functional TCR.
A recombinant or engineered cell according to any of the foregoing claims which comprises a suicide gene optionally expressed under the control of an inducible promoter.
A recombinant or engineered cell according to any of the foregoing claims which is further engineered to express at least one anti-oxidant, nerve growth factor or non classical neurotrophic factor the expression of which is optionally under the control of an inducible promoter.
A recombinant or engineered cell according to any of the foregoing claims which when administered crosses the BBB.
A recombinant or engineered cell according to any of the foregoing claims which possesses Treg effector functions.
A recombinant or engineered cell according to any of the foregoing claims which expresses Treg surface markers and/or expresses IL-10 or a viral variant of IL-10.
A recombinant or engineered cell according to any of the foregoing claims wherein at least one CAR is expressed on the surface thereof.
A recombinant or engineered cell according to any one of the foregoing claims, wherein at least one of the following constructs are expressed by said cell:
A recombinant or engineered cell according to any one of the foregoing claims, wherein at least one of the following constructs are expressed by said cell:
A recombinant or engineered cell according to any one of the foregoing claims, wherein at least one of the following constructs are expressed by said cell:
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject elicits one or more of the following properties at sites of neurodegeneration comprising the antigen bound by the CAR:
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease inhibits inflammation and/or produces anti-inflammatory mediators at sites of inflammation in the CNS.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease inhibits or prevents at least one of at a site of neurodegeneration:
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject at risk of developing a neurodegenerative disease slows the onset of the neurodegenerative disease.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease slows the progression of the neurodegenerative disease.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease repairs or increases neural cell function or slows the loss of neural cell function.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease increases cognition or inhibits or slows the loss of cognition in the treated subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease reduces or slows the loss of neuromotor function and/or paralysis in the treated subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease reduces the number or size of neural lesions or plaques in the treated subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject with a neurodegenerative disease reduces the number of or severity of seizures in the treated subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject expresses increased levels of IL-10 in response to mSOD1 antigen in the subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject expresses increased levels of the cell surface markers of any one or more of GITR, PD-1 and/or CTLA-4 in response to mSOD1 antigen in the subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject inhibits superoxide generation in response to mSOD1 antigen and/or anti-CD3 in the subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject inhibits TNF-α production in response to mSOD1 antigen in the subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject expresses increased levels of IL-10 and/or IL-4 in response to amyloid beta antigen in the subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject inhibits superoxide generation in response to amyloid beta antigen and/or anti-CD3 in the subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject inhibits IL-6 production in response to amyloid beta antigen and/or anti-CD3 in the subject.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject protects cells of the subject from hydrogen peroxide toxicity.
A recombinant or engineered cell according to any of the foregoing claims which when administered to a subject protects cells of the subject from hydrogen peroxide toxicity.
A composition suitable for therapy comprising recombinant or engineered cells according to any of the foregoing claims and a pharmaceutically acceptable carrier.
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or an NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (e.g. overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with Alzheimer's disease.
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or an NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with Alzheimer's disease, and a CAR of said CAR-expressing cells includes DG01 (SEQ ID NO:
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or an NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with Alzheimer's disease, and said cells are engineered to express any one or more of the following:
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or an NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with Alzheimer's disease, and a CAR of said CAR-expressing cells includes DG01 (SEQ ID NO:
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or an NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with ALS.
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or an NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with ALS, and a CAR of said CAR-expressing cells includes DG05 (SEQ ID NO:
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or an NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with ALS, and said cells are engineered to express any one or more of the following:
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or a NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with ALS, and a CAR of said CAR-expressing cells includes DG05 (SEQ ID NO:
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or a NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with Parkinson's disease.
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or a NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said cells are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with Parkinson's disease, and a CAR of said CAR-expressing cells includes D008 (SEQ ID NO:
A method of treating a subject comprising a neurodegenerative disease or condition, exhibiting one or more risk factors associated with the development of a neurodegenerative disease or condition, and/or exhibiting one or more signs or symptoms associated with the diagnosis of a neurodegenerative disease or condition, comprising administering an effective amount of cells which are engineered to express a chimeric antigen receptor (“CAR”) or a NDMM, wherein the CAR and the NDMM may be expressed by the same or different cells, which targets at least one (i) aberrant protein which is expressed in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition and/or (ii) a protein which is aberrantly expressed (overexpressed) in the central nervous system at site(s) of neurodegeneration associated with a specific neurodegenerative disease and is associated with the pathology of said specific neurodegenerative disease or condition, wherein said are administered under conditions whereby they are in contact with said site(s) of neurodegeneration comprising said targeted protein and thereby prevent, inhibit or treat the neurodegenerative disease or condition and/or one or more symptoms associated with the neurodegenerative disease or condition which is characterized by the expression of said aberrant or aberrantly expressed protein, wherein said targeted protein is a protein associated with Parkinson's disease, and a CAR of said CAR-expressing cells includes DG08 (SEQ ID NO:
A nucleic acid which encodes a chimeric antigen receptor (CAR) and optionally a NDMM comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said protein is a protein associated with Alzheimer's disease.
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said protein is a form of amyloid beta associated with Alzheimer's disease.
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said protein is a protein associated with ALS disease.
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said protein is mutated or aberrantly expressed SOD1.
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said protein is a protein associated with Parkinson's disease.
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said protein is a form of alpha-synuclein associated with Parkinson's disease.
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said nucleic acid encodes DG01 (SEQ ID NO:
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said nucleic acid encodes any one or more of the following:
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said nucleic acid encodes DG05 (SEQ ID NO:
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said nucleic acid encodes any one or more of the following constructs:
A nucleic acid which encodes a chimeric antigen receptor (CAR) comprising (i) at least one ligand binding moiety which binds to an aberrant protein associated with the pathology of a neurodegenerative disease or a protein which is aberrantly (overexpressed) in the central nervous system at site(s) of neurodegeneration which protein is associated with the pathology of a specific neurodegenerative disease or condition and (ii) optionally at least one signaling domain, e.g., a costimulatory signaling domain, and (iii) further optionally an NDMM, the expression of which are optionally controlled by the same or different inducible or constitutive promoters, wherein said nucleic acid encodes DG08 (SEQ ID NO:
Dependencies are inferred from the claim text.