# US 2020/0399354 A1 · Chimeric antigen receptors for treatment of neurodegenerative diseases and disorders

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- Number: US 2020/0399354 A1
- Document ID: US20200399354A1
- Status: Published application
- Kind: A1
- Application number: 16/968,451
- Filed: 2019-02-11
- Published: 2020-12-24
- Earliest claimed: 2018-02-09
- Assignees: Trustees of Dartmouth College
- Applicants: The Trustees of Dartmouth College
- Inventors: Charles SENTMAN; David GRABER; W. James COOK
- Web page: https://patentgrep.com/patent/US20200399354A1

## CPC

- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- C07K 16/18: against material from animals or humans
- A61K 39/0007: {Nervous system antigens; Prions}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/22: Immunosuppressive or immunotolerising
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/414: {Nervous system antigens}
- A61K 40/416: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 14/70521: {CD28, CD152}
- C12N 5/0637: {Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg}
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding
- C07K 2319/03: containing a transmembrane segment
- C12N 2510/00: Genetically modified cells
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The method of claim 1, wherein said site(s) of neurodegeneration are present in the central nervous system.

### Claim 3 (depends on 1)

The method of claim 1, wherein said site(s) of neurodegeneration are present in the peripheral nervous system.

### Claim 4 (depends on 1)

The method of claim 1, wherein said site(s) of neurodegeneration are present in the peripheral and the central nervous system.

### Claim 5

The method of any of the foregoing claims, wherein said CAR-expressing cells comprise immune cells.

### Claim 6 (depends on 5)

The method of claim 5, wherein said CAR-expressing immune cells comprise T cells or T cell progenitors, preferably T regulatory cells (Tregs) such as FOXP3+ Tregs.

### Claim 7

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.

### Claim 8

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.

### Claim 9

The method of any one of the foregoing claims, wherein the CAR comprised on said administered cells comprises DG01 (SEQ ID NO: 1), DG02 (SEQ ID NO: 2), DG03 (SEQ ID NO: 3), DG04 (SEQ ID NO: 4), DG05 (SEQ ID NO: 5), DG06 (SEQ ID NO: 6), and/or DG07 (SEQ ID NO: 7), DG08 (SEQ ID NO: 8), DG09 (SEQ ID NO: 9), DG10 (SEQ ID NO: 10), DG11 (SEQ ID NO: 11), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 10

The method of any one of the foregoing claims, wherein said administered cells are engineered to express one or more of the following constructs: DG05-CD28-CD3ζ (also referred to as DG05-28-3ζ) (SEQ ID NO: 24); DG05-CD28tm-DAP10-CD3ζ (also referred to as DG05-28tm-10-3ζ) (SEQ ID NO: 40); DG05-CD28tm-CD44-CD3ζ (also referred to as DG05-28tm-44-3ζ) (SEQ ID NO: 41); DG05-CD28tm-CD3ζ (also referred to as DG05-28tm-3ζ) (SEQ ID NO: 42); DG05-CD28 (also referred to as DG05-28) (SEQ ID NO: 43); DG05-CD28tm (also referred to as DG05-28tm) (SEQ ID NO: 44), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 11 (depends on 10)

The method of claim 10, wherein each of said one or more constructs targets mutSOD1.

### Claim 12

The method of any one of the foregoing claims, wherein said administered cells are engineered to express one or more of the following: DG03-CD28-CD3ζ (also referred to as DG03-28-3ζ) (SEQ ID NO: 22); DG03-CD28tm-DAP10-CD3ζ (also referred to as DG03-28tm-10-3ζ) (SEQ ID NO: 45); DG03-CD28tm-CD44-CD3ζ (also referred to as DG03-28tm-44-3ζ) (SEQ ID NO: 46); DG03-CD28tm-4-1-BB-CD3ζ (also referred to as DG03-28tm-BB-3ζ) (SEQ ID NO: 47); DG03-CD28tm-CD3ζ (also referred to as DG03-28tm-3ζ) (SEQ ID NO: 48); DG03-CD28 (also referred to as DG03-28) (SEQ ID NO: 49); DG03-CD28tm (also referred to as DG03-28tm) (SEQ ID NO: 50), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 13 (depends on 12)

The method of claim 12, wherein each of said one or more constructs targets amyloid beta.

### Claim 14

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.

### Claim 15

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: 51), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the aforementioned construct.

### Claim 16

The method of any one of the foregoing claims, wherein said administered cells are engineered to express human catalase (SEQ ID NO: 52), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the aforementioned construct.

### Claim 17

The method of any one of the foregoing claims, wherein said administered cells are engineered to express BDNF (SEQ ID NO: 53), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the aforementioned construct.

### Claim 18

The method of any one of the foregoing claims, wherein said administered cells are engineered to express IGF-1 (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the aforementioned construct.

### Claim 19

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.

### Claim 20 (depends on 19)

The method of claim 19, wherein the anti-oxidant also promotes T cell function or lifespan.

### Claim 21

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); a synucleinopathy; a tauopathy, a spongiform encephalopathy; familial amyloidotic polyneuropathy; Dutch hereditary cerebral hemorrhage with amyloidosis; congophilic angiopathy; corticobasal degeneration; Pick's disease; progressive supranuclear palsy; Creutzfeldt-Jacob disease; Gerstmann-Straussler-Schneiker syndrome; fatal familial insomnia; kuru; bovine spongiform encephalopathy; scrapie; chronic wasting disease; Lewy body variant of Alzheimer's disease; diffuse Lewy body disease; dementia with Lewy bodies; multiple system atrophy; neurodegeneration with brain iron accumulation type I; diffuse Lewy body disease; frontotemporal lobar degeneration; hereditary dentatorubral-pallidoluysian atrophy; Kennedy's disease; Alexander's disease; Cockayne syndrome; and Icelandic hereditary cerebral hemorrhage with amyloidosis.

### Claim 22

The method of any of the foregoing claims, wherein the neurodegenerative disease comprises Parkinson's disease.

### Claim 23

The method of any of the foregoing claims, wherein the neurodegenerative disease comprises Alzheimer's disease.

### Claim 24

The method of any of the foregoing claims, wherein the neurodegenerative disease comprises amyotrophic lateral sclerosis (ALS).

### Claim 25

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; TAR DNA-binding protein 43 (TDP-43): chromosome 9 open reading frame 72 (c9orf72); β-Synuclein; γ-Synuclein; RNA-binding protein fused in sarcoma (PUS); ubiquitin; ubiquilin-2, p62; optineurin; ataxin-2; parkin; Serine/threonine-protein kinase PINK1; and Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2), Huntingtin with tandem glutamine repeats; prion proteins; transthyretin; dentatorubral pallidoluysian atrophy (DRPLA) protein; androgen receptor; an ataxin; P/Q-type calcium channel α1A subunit; TATA-box-binding protein; glial fibrillary acidic protein; DNA excision repair protein ERCC-6; survival motor neuron protein; and cystatin C.

### Claim 26

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); interleukin-6 (IL-6); activated protein C (APC); thrombomodulin; tissue plasminogen activator (tPA); Protein deglycase DJ-1; a tissue inhibitor of metalloproteinases (TIMP), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), a bone morphogenetic protein (BMP), erythropoietin (EPO), thrombopoietin (TPO), and granulocyte-colony stimulating factor (G-CSF), optionally wherein said at least one pro-neuronal factor, neurotrophic factor, or nerve growth factor are expressed by the same cell as said CAR or by a different cell as said CAR.

### Claim 27

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; activity-dependent neuroprotector homeobox (ADNP); phycocyanin; neuroglobin, catalase, and NRF2, optionally wherein said at least one anti-oxidative protein is expressed by the same cell as said CAR or by a different cell as said CAR.

### Claim 28

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.

### Claim 29

The method of any of the foregoing claims, wherein the administered cells inhibit or prevent at least one of:
(i) microglia cell over-activation wherein over-activation includes microglia which possess at least one activity or increase in an activity characteristic of activated microglia such as (1) a change in morphology, (2) migration to inflammatory sites, (3) production of neurotoxic or inflammatory cytokines such as IL-1, (4) interaction with neural plaques or β amyloid deposits, (5) synthesis of neurotoxic proteins, (6) secretion of proteases and/or reactive oxygen species, (7) induction of amyloid production by neighboring cells, (8) destruction of myelin;
(ii) increased numbers of microglia;
(iii) the production of inflammatory proteins or inflammatory activities at sites of neurodegeneration; and/or
(iv) neuronal death or impaired neuronal function.

### Claim 30

The method of any of the foregoing claims, wherein the administered cells slow the onset of the neurodegenerative disease.

### Claim 31

The method of any of the foregoing claims, wherein the administered cells slow the progression of the neurodegenerative disease.

### Claim 32

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.

### Claim 33

The method of any of the foregoing claims, wherein the administered cells increase cognition or stabilize the loss of cognition in the treated subject.

### Claim 34

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.

### Claim 35

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.

### Claim 36

The method of any of the foregoing claims, wherein the administered cells reduce the number of or severity of seizures in the treated subject.

### Claim 37

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.

### Claim 38

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.

### Claim 39

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.

### Claim 40

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.

### Claim 41 (depends on 37, 38, 39, 40)

The method of any one of claims 37-40, wherein said administered cells are engineered to express a construct comprising DG05 (SEQ ID NO: 5), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the aforementioned construct.

### Claim 42 (depends on 37, 38, 39, 40)

The method of any one of claims 37-40, wherein said administered cells are engineered to express one or more of the following constructs: DG05-CD28-CD3 (also referred to as DG05-28-3ζ) (SEQ ID NO: 24); DG05-CD28tm-DAP10-CD3ζ (also referred to as DG05-28tm-10-3ζ) (SEQ ID NO: 40); DG05-CD28tm-CD44-CD3ζ (also referred to as DG05-28tm-44-3ζ) (SEQ ID NO: 41); DG05-CD28tm-CD3ζ (also referred to as DG05-28tm-3ζ) (SEQ ID NO: 42); DG05-CD28 (also referred to as DG05-28) (SEQ ID NO: 43); DG05-CD28tm (also referred to as DG05-28tm) (SEQ ID NO: 44), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 43

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.

### Claim 44

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.

### Claim 45

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.

### Claim 46

The method of any one of the foregoing claims, wherein the administered cells protect cells of the treated subject from hydrogen peroxide toxicity.

### Claim 47 (depends on 43, 44, 45, 46)

The method of any one of claims 43-46, wherein the administered cells are engineered to express a construct comprising DG03 (SEQ ID NO: 3).

### Claim 48 (depends on 43, 44, 45, 46, 47)

The method of any one of claims 43-47, wherein the administered cells are engineered to express one or more of the following: DG03-CD28-CD3ζ (also referred to as DG03-28-3ζ) (SEQ ID NO: 22); DG03-CD28tm-DAP10-CD3ζ (also referred to as DG03-28tm-10-3ζ) (SEQ ID NO: 45); DG03-CD28tm-CD44-CD3ζ (also referred to as DG03-28tm-44-3ζ) (SEQ ID NO: 46); DG03-CD28tm-4-1-BB-CD3ζ (also referred to as DG03-28tm-BB-3ζ) (SEQ ID NO: 47); DG03-CD28tm-CD3ζ (also referred to as DG03-28tm-3ζ) (SEQ ID NO: 48); DG03-CD28 (also referred to as DG03-28) (SEQ ID NO: 49); DG03-CD28tm (SEQ ID NO: 50), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 49

The method of any one of the foregoing claims, wherein the administered cells protect cells of the treated subject from hydrogen peroxide toxicity.

### Claim 50 (depends on 49)

The method of claim 49, wherein the administered cells are engineered to express one or more of the following constructs: NDMM human catalase construct (SEQ ID NO: 52), NDMM Nrf2 (Keap1 inhibitor peptide) construct (SEQ ID NO: 51), NDMM BDNF construct (SEQ ID NO: 53), NDMM IGF-1 construct (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 51

The method of any of the foregoing claims, wherein the cells are administered systemically or locally.

### Claim 52

The method of any of the foregoing claims, wherein the cells cross the blood brain barrier (BBB).

### Claim 53

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.

### Claim 54

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.

### Claim 55

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.

### Claim 56

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.

### Claim 57

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.

### Claim 58

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.

### Claim 59

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.

### Claim 60

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.

### Claim 61 (depends on 60)

The nucleic acid of claim 60, wherein the protein associated with a neurodegenerative disease or condition is selected from human amyloid beta, amyloid-beta 1-42, alpha-synuclein, superoxide dismutase-1 (SOD-1), hyperphosphorylated tau protein; TAR DNA-binding protein 43 (TDP-43): chromosome 9 open reading frame 72 (c9orf72); β-Synuclein; γ-Synuclein; RNA-binding protein fused in sarcoma (FUS); ubiquitin; ubiquilin-2, p62; optineurin; ataxin-2; parkin; Serine/threonine-protein kinase PINK1; and Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2), Huntingtin with tandem glutamine repeats; prion proteins; transthyretin; dentatorubral pallidoluysian atrophy (DRPLA) protein; androgen receptor; an ataxin; P/Q-type calcium channel α1A subunit; TATA-box-binding protein; glial fibrillary acidic protein; DNA excision repair protein ERCC-6; survival motor neuron protein; and cystatin C.

### Claim 62 (depends on 60, 61)

The nucleic acid of claim 60 or 61, wherein the protein associated with a neurodegenerative disease or condition comprises one or more of an amyloid protein, e.g, amyloid-beta protein, or a mutant superoxide dismutase 1, or human alpha-synuclein.

### Claim 63

The nucleic acid of any of the foregoing claims, which further encodes human catalase and/or the Neh2 domain of human Nrf2.

### Claim 64

The nucleic acid of any of the foregoing claims, which further encodes human IGF-1.

### Claim 65

The nucleic acid of any of the foregoing claims, which further encodes human BDNF.

### Claim 66

The nucleic acid of any one of the foregoing claims, which further encodes one or more of the following constructs: NDMM Nrf2 (Keap1 inhibitor peptide) (SEQ ID NO: 51); NDMM human catalase (SEQ ID NO: 52); NDMM BDNF (SEQ ID NO: 53); and/or NDMM IGF-1 (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 67

The nucleic acid of any of the foregoing claims, wherein a ligand binding domain in the CAR comprises a scFv.

### Claim 68

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.

### Claim 69

The nucleic acid of any of the foregoing claims, which encodes one or more of the following: DG01 (SEQ ID NO: 1), DG02 (SEQ ID NO: 2), DG03 (SEQ ID NO: 3), DG04 (SEQ ID NO: 4), DG05 (SEQ ID NO: 5), DG06 (SEQ ID NO: 6), DG07 (SEQ ID NO: 7), DG08 (SEQ ID NO: 8), DG09 (SEQ ID NO: 9), DG10 (SEQ ID NO: 10), DG11 (SEQ ID NO: 11), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 70

The nucleic acid of any of the foregoing claims, which encodes one or more of the following: DG05-CD28-CD3ζ (also referred to as DG05-28-3ζ) (SEQ ID NO: 24); DG05-CD28tm-DAP10-CD3ζ (also referred to as DG05-28tm-10-3ζ) (SEQ ID NO: 40); DG05-CD28tm-CD44-CD3ζ (also referred to as DG05-28tm-44-3ζ) (SEQ ID NO: 41); DG05-CD28tm-CD3ζ (also referred to as DG05-28tm-3ζ) (SEQ ID NO: 42); DG05-CD28 (also referred to as DG05-28) (SEQ ID NO: 43); DG05-CD28tm (also referred to as DG05-28tm) (SEQ ID NO: 44), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 71

The nucleic acid of any of the foregoing claims, which encodes one or more of the following: DG03-CD28-CD3ζ (also referred to as DG03-28-3ζ) (SEQ ID NO: 22); DG03-CD28tm-DAP10-CD3ζ (also referred to as DG03-28tm-10-3ζ) (SEQ ID NO: 45); DG03-CD28tm-CD44-CD3ζ (also referred to as DG03-28tm-44-3ζ) (SEQ ID NO: 46); DG03-CD28tm-4-1-BB-CD3ζ (also referred to as DG03-28tm-BB-3ζ) (SEQ ID NO: 47); DG03-CD28tm-CD3ζ (also referred to as DG03-28tm-3ζ) (SEQ ID NO: 48); DG03-CD28 (also referred to as D003-28) (SEQ ID NO: 49); DG03-CD28tm (also referred to as DG03-28tm) (SEQ ID NO: 50), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 72

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.

### Claim 73

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.

### Claim 74

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.

### Claim 75

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); a synucleinopathy; a tauopathy, a spongiform encephalopathy; familial amyloidotic polyneuropathy; Dutch hereditary cerebral hemorrhage with amyloidosis; congophilic angiopathy; corticobasal degeneration; Pick's disease; progressive supranuclear palsy; Creutzfeldt-Jacob disease; Gerstmann-Straussler-Schneiker syndrome; fatal familial insomnia; kuru; bovine spongiform encephalopathy; scrapie; chronic wasting disease; Lewy body variant of Alzheimer's disease; diffuse Lewy body disease; dementia with Lewy bodies; multiple system atrophy; neurodegeneration with brain iron accumulation type I; diffuse Lewy body disease; frontotemporal lobar degeneration; hereditary dentatorubral-pallidoluysian atrophy; Kennedy's disease; Alexander's disease; Cockayne syndrome; and Icelandic hereditary cerebral hemorrhage with amyloidosis.

### Claim 76

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.

### Claim 77

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.

### Claim 78

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).

### Claim 79

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; TAR DNA-binding protein 43 (TDP-43): chromosome 9 open reading frame 72 (c9orf72); β-Synuclein; γ-Synuclein; RNA-binding protein fused in sarcoma (FUS); ubiquitin; ubiquilin-2, p62; optineurin; ataxin-2; parkin; Serine/threonine-protein kinase PINK1; and Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2), Huntingtin with tandem glutamine repeats; prion proteins; transthyretin; dentatorubral pallidoluysian atrophy (DRPLA) protein; androgen receptor; an ataxin; P/Q-type calcium channel α1A subunit; TATA-box-binding protein; glial fibrillary acidic protein; DNA excision repair protein ERCC-6; survival motor neuron protein; and cystatin C.

### Claim 80

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); interleukin-6 (IL-6); activated protein C (APC); thrombomodulin; tissue plasminogen activator (tPA); Protein deglycase DJ-1; a tissue inhibitor of metalloproteinases (TIMP), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), a bone morphogenetic protein (BMP), erythropoietin (EPO), thrombopoietin (TPO), and granulocyte-colony stimulating factor (G-CSF).

### Claim 81

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; activity-dependent neuroprotector homeobox (ADNP); phycocyanin; neuroglobin, catalase, and NRF2.

### Claim 82

A recombinant or engineered cell which comprises at least one nucleic acid encoding a CAR according to any of the foregoing cells.

### Claim 83 (depends on 82)

The cell of claim 82, which comprises a human immune cell, e.g., a T cell or T cell progenitor or an NK cell.

### Claim 84 (depends on 82)

The cell of claim 82, which comprises a Treg cell, e.g., a FoxP3+ Treg cell.

### Claim 85

A recombinant or engineered cell according to any of the foregoing claims which does not express a functional TCR.

### Claim 86

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.

### Claim 87

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.

### Claim 88

A recombinant or engineered cell according to any of the foregoing claims which when administered crosses the BBB.

### Claim 89

A recombinant or engineered cell according to any of the foregoing claims which possesses Treg effector functions.

### Claim 90

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.

### Claim 91

A recombinant or engineered cell according to any of the foregoing claims wherein at least one CAR is expressed on the surface thereof.

### Claim 92

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: DG01 (SEQ ID NO: 1), DG02 (SEQ ID NO: 2), D003 (SEQ ID NO: 3), DG04 (SEQ ID NO: 4), DG05 (SEQ ID NO: 5), DG06 (SEQ ID NO: 6), and/or DG07 (SEQ ID NO: 7), DG08 (SEQ ID NO: 8), DG09 (SEQ ID NO: 9), DG10 (SEQ ID NO: 10), DG11 (SEQ ID NO: 11), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 93

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: DG05-CD28-CD3ζ (also referred to as DG05-28-3ζ) (SEQ ID NO: 24); DG05-CD28tm-DAP10-CD3ζ (also referred to as DG05-28tm-10-3ζ) (SEQ ID NO: 40); DG05-CD28tm-CD44-CD3ζ (also referred to as DG05-28tm-44-3ζ) (SEQ ID NO: 41); DG05-CD28tm-CD3ζ (also referred to as DG05-28tm-3ζ) (SEQ ID NO: 42); D005-CD28 (also referred to as DG05-28) (SEQ ID NO: 43); DG05-CD28tm (also referred to as D005-28tm) (SEQ ID NO: 44), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 94

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: NDMM Nrf2 (Keap1 inhibitor peptide) (SEQ ID NO: 51); NDMM human catalase (SEQ ID NO: 52); NDMM BDNF (SEQ ID NO: 53); NDMM IGF-1 (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 95

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: (i) inhibits macrophage activity or activation (wherein over-activation includes microglia which possess at least one activity or increase in an activity characteristic of activated microglia such as (1) a change in morphology, (2) migration to inflammatory sites, (3) production of neurotoxic or inflammatory cytokines such as IL-1, (4) interaction with neural plaques or β amyloid deposits, (5) synthesis of neurotoxic proteins, (6) secretion of proteases and/or reactive oxygen species, (7) induction of amyloid production by neighboring cells, (8) destruction of myelin), (ii) inhibits macrophages, (iii) inhibits secretion of inflammatory cytokines, proteases, and oxidants such as IL-1β, TNFα, NO and other neurotoxins by macrophages or microglia, (iv) promotes secretion of secretes more of one or more of IL-10, IL-4, and TGF-beta, and (v) inhibits inflammation or neurodegeneration.

### Claim 96

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.

### Claim 97

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:
(i) microglia cell over-activation (as above-defined),
(ii) neurotoxic macrophage activity and/or secretion of neurotoxic moieties thereby;
(iii) loss of neuronal function;
(iv) increased microglia cell number or macrophage number;
(v) the production of inflammatory proteins or inflammatory activities at sites of neurodegeneration, and
(vi) neuronal death.

### Claim 98

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.

### Claim 99

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.

### Claim 100

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.

### Claim 101

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.

### Claim 102

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.

### Claim 103

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.

### Claim 104

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.

### Claim 105

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.

### Claim 106

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.

### Claim 107

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.

### Claim 108

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.

### Claim 109 (depends on 105, 106, 107, 108)

The recombinant or engineered cell according to any of claims 105-108, wherein said cell is engineered to express a construct comprising D005 (SEQ ID NO: 5).

### Claim 110 (depends on 105, 106, 107, 108, 109)

The recombinant or engineered cell according to any of claims 105-109, wherein said cell is engineered to express one or more of the following constructs: DG05-CD28-CD3ζ (also referred to as DG05-28-3ζ) (SEQ ID NO: 24); DG05-CD28tm-DAP10-CD3ζ (also referred to as DG05-28tm-10-3ζ) (SEQ ID NO: 40); DG05-CD28tm-CD44-CD3ζ (also referred to as DG05-28tm-44-3ζ) (SEQ ID NO: 41); DG05-CD28tm-CD3ζ (also referred to as DG05-28tm-3ζ) (SEQ ID NO: 42); DG05-CD28 (also referred to as DG05-28) (SEQ ID NO: 43); DG05-CD28tm (also referred to as DG05-28tm) (SEQ ID NO: 44), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 111

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.

### Claim 112

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.

### Claim 113

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.

### Claim 114

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.

### Claim 115 (depends on 111, 112, 113, 114)

The recombinant or engineered cell according to any of claims 111-114, wherein said cell is engineered to express a construct comprising D003 (SEQ ID NO: 3).

### Claim 116 (depends on 111, 112, 113, 114, 115)

The recombinant or engineered cell according to any of claims 111-115, wherein said cell is engineered to express one or more of the following: DG03-CD28-CD3ζ (also referred to as DG03-28-3ζ) (SEQ ID NO: 22); D003-CD28tm-DAP10-CD3ζ (also referred to as DG03-28tm-10-3ζ) (SEQ ID NO: 45); DG03-CD28tm-CD44-CD3ζ (also referred to as D003-28tm-44-3ζ) (SEQ ID NO: 46); DG03-CD28tm-4-1-BB-CD3ζ (also referred to as DG03-28tm-BB-3ζ) (SEQ ID NO: 47); DG03-CD28tm-CD3ζ (also referred to as DG03-28tm-3ζ) (SEQ ID NO: 48); DG03-CD28 (also referred to as DG03-28) (SEQ ID NO: 49); DG03-CD28tm (SEQ ID NQ: 50), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 117

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.

### Claim 118 (depends on 117)

The recombinant or engineered cell of claim 117, wherein said cell is engineered to express one or more of the following constructs: NDMM human catalase construct (SEQ ID NO: 52), NDMM Nrf2 (Keap1 inhibitor peptide) construct (SEQ ID NO: 51), NDMM BDNF construct (SEQ ID NO: 53), NDMM IGF-1 construct (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 119

A composition suitable for therapy comprising recombinant or engineered cells according to any of the foregoing claims and a pharmaceutically acceptable carrier.

### Claim 120 (depends on 75)

The composition of claim 75, which further comprises at least one stabilizer.

### Claim 121 (depends on 75, 76)

The composition of claim 75 or 76 which comprises an additive that promotes the ability of the cells contained therein to cross the BBB or the cells are attached or complexed with a moiety additive that promotes the ability of the cells to cross the BBB.

### Claim 122

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.

### Claim 123

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: 1), DG02 (SEQ ID NO: 2), DG03 (SEQ ID NO: 3), DG04 (SEQ ID NO: 4), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 124

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: DG03 (SEQ ID NO: 3); DG03-CD28-CD3ζ (also referred to as DG03-28-3ζ) (SEQ ID NO: 22); DG03-CD28tm-DAP10-CD3ζ (also referred to as DG03-28tm-10-3ζ) (SEQ ID NO: 45); D003-CD28tm-CD44-CD3ζ (also referred to as DG03-28tm-44-3ζ) (SEQ ID NO: 46); DG03-CD28tm-4-1-BB-CD3ζ (also referred to as DG03-28tm-BB-3ζ) (SEQ ID NO: 47); DG03-CD28tm-CD3ζ (also referred to as DG03-28tm-3ζ) (SEQ ID NO: 48); DG03-CD28 (also referred to as DG03-28) (SEQ ID NO: 49); DG03-CD28tm (SEQ ID NO: 50), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 125

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: 1), DG02 (SEQ ID NO: 2), DG03 (SEQ ID NO: 3), DG04 (SEQ ID NO: 4), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs, and further wherein said cells are engineered to express one or more neurodegenerative disease modifying molecules (NDMMs).

### Claim 126 (depends on 125)

The method of claim 125, wherein said cells are engineered to express one or more of the following constructs: NDMM human catalase construct (SEQ ID NO: 52), NDMM Nrf2 (Keap1 inhibitor peptide) construct (SEQ ID NO: 51), NDMM BDNF construct (SEQ ID NO: 53), and/or NDMM IGF-1 construct (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 127

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.

### Claim 128

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: 5), DG06 (SEQ ID NO: 6), DG07 (SEQ ID NO: 7), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 129

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: DG05 (SEQ ID NO: 5); DG05-CD28-CD3ζ (also referred to as DG05-28-3ζ) (SEQ ID NO: 24); DG05-CD28tm-DAP10-CD3ζ (also referred to as DG05-28tm-10-3ζ) (SEQ ID NO: 40); DG05-CD28tm-CD44-CD3ζ (also referred to as DG05-28tm-44-3ζ) (SEQ ID NO: 41); DG05-CD28tm-CD3ζ (also referred to as DG05-28tm-3ζ) (SEQ ID NO: 42); DG05-CD28 (also referred to as DG05-28) (SEQ ID NO: 43); DG05-CD28tm (also referred to as D005-28tm) (SEQ ID NO: 44), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 130

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: 5), DG06 (SEQ ID NO: 6), DG07 (SEQ ID NO: 7), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs, and further wherein said cells are engineered to express one or more neurodegenerative disease modifying molecules (NDMMs).

### Claim 131 (depends on 130)

The method of claim 130, wherein said cells are engineered to express one or more of the following constructs: NDMM human catalase construct (SEQ ID NO: 52), NDMM Nrf2 (Keap1 inhibitor peptide) construct (SEQ ID NO: 51), NDMM BDNF construct (SEQ ID NO: 53), NDMM IGF-1 construct (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 132

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.

### Claim 133

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: 8), DG09 (SEQ ID NO: 9), DG10 (SEQ ID NO: 10), DG11 (SEQ ID NO: 11), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 134

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: 8), DG09 (SEQ ID NO: 9), D010 (SEQ ID NO: 10), DG11 (SEQ ID NO: 11), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs, and further wherein said cells are engineered to express one or more neurodegenerative disease modifying molecules (NDMMs).

### Claim 135 (depends on 134)

The method of claim 134, wherein said cells are engineered to express one or more of the following constructs: NDMM human catalase construct (SEQ ID NO: 52), NDMM Nrf2 (Keap1 inhibitor peptide) construct (SEQ ID NO: 51), NDMM BDNF construct (SEQ ID NO: 53), NDMM IGF-1 construct (SEQ ID NO: 54), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 136

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.

### Claim 137

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.

### Claim 138

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.

### Claim 139

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.

### Claim 140

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.

### Claim 141

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.

### Claim 142

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: 1), D002 (SEQ ID NO: 2), DG03 (SEQ ID NO: 3), DG04 (SEQ ID NO: 4), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 143

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: DG03-CD28-CD3ζ (also referred to as DG03-28-3ζ) (SEQ ID NO: 22); D003-CD28tm-DAP10-CD3ζ (also referred to as DG03-28tm-10-3ζ) (SEQ ID NO: 45); DG03-CD28tm-CD44-CD3ζ (also referred to as DG03-28tm-44-3ζ) (SEQ ID NO: 46); DG03-CD28tm-4-1-BB-CD3ζ (also referred to as DG03-28tm-BB-3ζ) (SEQ ID NO: 47); DG03-CD28tm-CD3ζ (also referred to as DG03-28tm-3ζ) (SEQ ID NO: 48); DG03-CD28 (also referred to as DG03-28) (SEQ ID NO: 49); D003-CD28tm (SEQ ID NO: 50), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 144

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: 5), DG06 (SEQ ID NO: 6), DG07 (SEQ ID NO: 7), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 145

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: DG05-CD28-CD3ζ (also referred to as DG05-28-3ζ) (SEQ ID NO: 24); DG05-CD28tm-DAP10-CD3ζ (also referred to as DG05-28tm-10-3ζ) (SEQ ID NO: 40); DG05-CD28tm-CD44-CD3ζ (also referred to as DG05-28tm-44-3ζ) (SEQ ID NO: 41); DG05-CD28tm-CD3ζ (also referred to as DG05-28tm-3t) (SEQ ID NO: 42); DG05-CD28 (also referred to as DG05-28) (SEQ ID NO: 43); D005-CD28tm (also referred to as DG05-28tm) (SEQ ID NO: 44), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 146

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: 8), DG09 (SEQ ID NO: 9), DG10 (SEQ ID NO: 10), DG11 (SEQ ID NO: 11), and/or a construct comprising at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to any one or more of the aforementioned constructs.

### Claim 147 (depends on 136)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 136.

### Claim 148 (depends on 137)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 137.

### Claim 149 (depends on 138)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 138.

### Claim 150 (depends on 139)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 139.

### Claim 151 (depends on 140)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 140.

### Claim 152 (depends on 141)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 141.

### Claim 153 (depends on 142)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 142.

### Claim 154 (depends on 143)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 143.

### Claim 155 (depends on 144)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 144.

### Claim 156 (depends on 145)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 145.

### Claim 157 (depends on 146)

A modified Treg which comprises a nucleic acid which encodes a chimeric antigen receptor (CAR) according to claim 146.