Compositions and methods for increasing or enhancing the transduction of gene therapy vectors to remove or reduce immunoglobulins

Abstract

A method for treating patients who may have developed or already have neutralizing antibodies against gene therapy vectors by administering a protease that cleaves peptide bonds present in immunoglobulins, or by administering a glycosidase. [Solution] A method for treating a subject requiring treatment for a disease caused by loss of protein function or activity, comprising: (a) administering a recombinant viral vector to the subject containing a heterologous polynucleotide encoding a protein or peptide that provides or supplements the function or activity of a protein; and (b) administering to the subject an amount of protease or glycosidase effective in degrading, digesting and / or inhibiting or reducing the effector function of an antibody bound to the protein or peptide encoded by the recombinant viral vector and / or heterologous polynucleotide.

Claims

1. A method for treating a subject requiring treatment for a disease caused by loss of protein function or activity, comprising: (a) administering to the subject a recombinant viral vector comprising heterologous polynucleotide encoding a protein or peptide that provides or supplements protein function or activity; and (b) administering to the subject an amount of protease or glycosidase effective in degrading, digesting and / or inhibiting or reducing the effector function of an antibody bound to the protein or peptide encoded by the recombinant viral vector and / or heterologous polynucleotide.

2. A method for treating a subject requiring treatment for a disease caused by the acquisition of functional activity or expression, comprising: (a) administering to the subject a recombinant viral vector comprising heterologous polynucleotides transcribed into nucleic acids that inhibit, reduce, or decrease the expression of the acquisition of function, activity, or expression of the protein; and (b) administering to the subject a protease or glycosidase effective in degrading, digesting and / or inhibiting or reducing the effector function of an antibody bound to the recombinant viral vector.

3. A method for treating a subject requiring treatment for a disease caused by loss of function or activity of a protein, comprising: (a) administering to the subject a protease or glycosidase effective in degrading, digesting and / or inhibiting or reducing the effector function of a viral vector-conjugated antibody; and (b) administering to the subject a recombinant viral vector comprising a heterologous polynucleotide encoding a protein or peptide that provides or supplements the function or activity of the protein.

4. A method for treating a subject requiring treatment for a disease caused by the acquisition of functional activity or expression of a protein, comprising: (a) administering to the subject a protease or glycosidase effective in degrading, digesting and / or inhibiting or reducing the effector function of a viral vector-conjugated antibody; and (b) administering to the subject a recombinant viral vector comprising a heterologous polynucleotide transcribed into nucleic acid that inhibits, reduces or diminishes the acquisition of function, activity or expression of the protein.

5. The method according to claim 1 or 2, wherein step (b) is performed within approximately 90 days after step (a) is performed.

6. The method according to any one of claims 1 to 5, wherein the protease comprises a cysteine ​​protease or a thiol protease.

7. The method according to any one of claims 1 to 5, wherein the protease comprises a protease from Streptococcus piogenes, Streptococcus equi, or Mycoplasma canis.

8. The method according to any one of claims 1 to 5, wherein the protease comprises IdeS or a modified variant thereof as described in any of SEQ ID NOs: 3 to 18, 23, or 48.

9. The method according to any one of claims 1 to 5, wherein the glycosidase includes endoglycosidase.

10. The method according to claim 9, wherein the endoglycosidase comprises the sequence described in any of SEQ ID NOs: 44 to 47.

11. The method according to any one of claims 1 to 10, wherein the protease or glycosidase degrades, digests and / or inhibits or reduces the effector function of the human antibody.

12. The method according to any one of claims 1 to 11, wherein the viral vector comprises a lentiviral vector, an adenovirus vector, or an adeno-associated virus (AAV) vector.

13. The method according to claim 12, wherein the lentiviral vector comprises an envelope protein to which an antibody binds.

14. The method according to claim 12, wherein the AAV vector comprises a capsid protein to which an antibody binds.

15. The method according to claim 12, wherein the AAV vector comprises VP1, VP2, and / or VP3 capsid proteins to which the antibody binds.

16. The method according to any one of claims 12 to 15, wherein the AAV vector comprises VP1, VP2 and / or VP3 capsid proteins having 60% or more sequence identity with VP1, VP2 and / or VP3 capsid proteins selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV3B, AAV-2i8, Rh10, Rh74, SEQ ID NO: 1 and SEQ ID NO: 2 VP1, VP2 and / or VP3 capsid proteins.

17. The method according to any one of claims 12 to 15, wherein the AAV vector comprises VP1, VP2 and / or VP3 capsid proteins selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV3B, AAV-2i8, Rh10, Rh74, SEQ ID NO: 1 and SEQ ID NO: 2 VP1, VP2 and / or VP3 capsid proteins.

18. The method according to any one of claims 1, 3, and 5 to 17, wherein the subject has an antibody that binds to the viral vector.

19. The method according to any one of claims 1, 3, and 5 to 17, wherein the antibody that binds to the viral vector is not present in the subject.

20. The method according to any one of claims 1, 3, and 5 to 19, wherein the subject has an antibody that binds to a protein or peptide encoded by a heterogeneous polynucleotide.

21. The method according to any one of claims 1 to 20, wherein the antibody comprises IgG, IgM, IgA, IgD and / or IgE.

22. The method according to any one of claims 1 to 21, further comprising determining the presence of a viral vector-conjugated antibody in the subject before performing step (a), after performing step (a) but before performing step (b), and / or after performing steps (a) and (b), and quantifying its amount or effector function.

23. The method according to any one of claims 1 to 21, further comprising analyzing a biological sample from the subject for the presence, quantity, or effector function of viral vector-conjugated antibodies present in the sample before performing step (a), before performing step (a), before performing step (b), and / or after performing steps (a) and (b).

24. The method according to claim 23, wherein the biological sample from the subject is a blood product.

25. The method according to any one of claims 1 to 24, wherein the method results in a reduction of 20-50%, 50-75%, 75-90%, 90-95%, or 95% or more of the viral vector-conjugated antibody.

26. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than approximately 1:100,000 when one part of the biological sample or blood product is diluted with 100,000 parts of buffer, resulting in 50% viral vector neutralization.

27. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than approximately 1:50,000 when one part of the biological sample or blood product is diluted with 50,000 parts of buffer, resulting in 50% viral vector neutralization.

28. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than approximately 1:10,000 when one part of the biological sample or blood product is diluted with 10,000 parts of buffer, resulting in 50% viral vector neutralization.

29. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than approximately 1:1,000 when one part of the biological sample or blood product is diluted with 1,000 parts of buffer, resulting in 50% viral vector neutralization.

30. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than approximately 1:100 when one part of the biological sample or blood product is diluted with 100 parts of buffer, resulting in 50% viral vector neutralization.

31. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than about 1:10 when one part of the biological sample or blood product is diluted with 10 parts of buffer, resulting in 50% viral vector neutralization.

32. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than about 1:5 when one part of the biological sample or blood product is diluted with five parts of buffer, resulting in 50% viral vector neutralization.

33. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than about 1:4 when one part of the biological sample or blood product is diluted with four parts of buffer, resulting in 50% viral vector neutralization.

34. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than approximately 1:3 when one part of the biological sample or blood product is diluted with three parts of buffer, resulting in 50% viral vector neutralization.

35. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than about 1:2 when one part of the biological sample or blood product is diluted with two parts of buffer, resulting in 50% viral vector neutralization.

36. The method according to claim 23 or 24, wherein the viral vector-conjugated antibody present in the biological sample or blood product from the subject is less than approximately 1:1 when one part of the biological sample or blood product is diluted with one part of buffer, resulting in 50% viral vector neutralization.

37. The method according to any one of claims 1, 3, and 5-36, further comprising determining or quantifying the presence of an antibody bound to the polypeptide or peptide encoded by the heterogeneous polynucleotide after performing step (a) and before performing step (b), and / or after performing steps (a) and (b).

38. The method according to any one of claims 2 and 4 to 36, further comprising determining or quantifying the presence of an antibody that binds to the nucleic acid after performing step (a) and before performing step (b), and / or after performing steps (a) and (b).

39. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 60 days before or after step (a).

40. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 45 days before or after step (a).

41. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 30 days before or after step (a).

42. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 21 days before or after step (a).

43. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 14 days before or after step (a).

44. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 7 days before or after step (a).

45. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 72 hours before or after step (a).

46. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 48 hours before or after step (a).

47. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 24 hours before or after step (a).

48. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 12 hours before or after step (a).

49. The method according to any one of claims 1 to 38, wherein step (b) is performed within approximately 6 hours before or after step (a).

50. The aforementioned subjects include lung diseases (e.g., cystic fibrosis), hemorrhagic disorders (e.g., hemophilia A or hemophilia B with or without inhibitors), thalassemia, blood disorders (e.g., anemia), Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), epilepsy, lysosomal storage disorders (e.g., aspartylglucosamineuria, Batten's disease, late infant ceroid lipofuscinosis type 2 (CLN2), cystinosis, Fabry, Goucher disease types I, II, and III, glycogen storage disorder type II (Pompe disease), GM2-gangliosidosis type I (Taysachs disease), GM2-gangliosidosis type II (Sandhoff disease), mucolipidosis type I (sialidosis types I and II)), II (I-cell disease), III (pseudo-Herzheimer's disease) The method according to any one of claims 1 to 49, relating to having a Hurler's disease (and IV), mucopolysaccharidosis (Hurler's disease and variants, Hunter's, Sanfilippo types A, B, C, D, Morquio types A and B, Malotoramy and Sleigh's disease), Niemann-Pick disease types A / B, C1 and C2, and S. Tchindler's disease types I and II), hereditary angioedema (HAE), copper or iron storage disorders (e.g., Wilson's disease or Menkes disease), lysosomal acid lipase deficiency, neuropathy or neurodegenerative disorders, cancer, type 1 or type 2 diabetes, adenosine deaminase deficiency, metabolic disorders (e.g., glycogen storage disease), diseases of solid organs (e.g., brain, liver, kidney, heart), or infectious viruses (e.g., hepatitis B and C, HIV, etc.), bacterial or fungal diseases.

51. The method according to any one of claims 1 to 49, wherein the subject has a blood coagulation disorder.

52. The method according to any one of claims 1 to 49, wherein the subject has a deficiency in hemophilia A, hemophilia A and inhibitory antibodies, hemophilia B, hemophilia B and inhibitory antibodies, any coagulation factor: VII, VIII, IX, X, XI, V, XII, II, von Willebrand factor or a combination of FV / FVIII deficiencies, thalassemia, vitamin K epoxydoreductase C1 deficiency, or gamma carboxylase deficiency.

53. The method according to any one of claims 1 to 49, wherein the disease is anemia, trauma-related bleeding, injury, thrombosis, thrombocytopenia, stroke, coagulation disorders, disseminated intravascular coagulation (DIC); heparin, low molecular weight heparin, pentasaccharide, warfarin, small molecule antithrombotic agents (i.e., FXa inhibitors), or excessive anticoagulation associated with platelet disorders such as Bernard-Sulier syndrome, Glanzmann thrombasthenia, or storage pool deficiency.

54. Heterogeneous polynucleotides are used to produce insulin, glucagon, growth hormone (GH), parathyroid hormone (PTH), growth hormone-releasing factor (GRF), follicular-stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG), vascular endothelial growth factor (VEGF), angiopoietin, angiostatin, granulocyte colony-stimulating factor (GCSF), erythropoietin (EPO), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), acid fibroblast growth factor (aFGF), epidermal growth factor (EGF), transformed growth factor α (TGFα), platelet-derived growth factor (PDGF), insulin The method according to any one of claims 1 or 3 to 53, encoding a protein selected from the group consisting of growth factors I and II (IGF-I and IGF-II), TGFβ, activin, inhibin, bone morphogenesis protein (BMP), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin NT-3 and NT-4 / 5, ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), neuroturin, agrin, netrin-1 and netrin-2, hepatocyte growth factor (HGF), ephrin, noggin, sonic hedgehog, and tyrosine hydroxylase.

55. The method according to any one of claims 1 or 3 to 53, wherein the heterologous polynucleotide encodes a protein selected from the group consisting of thrombopoietin (TPO), interleukins (IL-1 to IL-36), monocyte chemoattractant proteins, leukemia inhibitors, granulocyte-macrophage colony-stimulating factors, Fas ligands, tumor necrosis factors α and β, interferon α, β, and γ, stem cell factors, flk-2 / flt3 ligands, IgG, IgM, IgA, IgD, and IgE, chimeric immunoglobulins, humanized antibodies, single-chain antibodies, T cell receptors, chimeric T cell receptors, single-chain T cell receptors, and class I and class II MHC molecules.

56. Heterogeneous polynucleotides include CFTR (cystic fibrosis transmembrane regulatory protein), blood coagulation (clotting) factors (factor XIII, factor IX, factor VIII, factor X, factor VII, factor VIIa, protein C, etc.), acquired blood coagulation factors, antibodies, retinal pigment epithelium-specific 65 kDa protein (RPE65), erythropoietin, LDL receptor, lipoprotein lipase, ornithine transcarbamylase, β-globin, α-globin, spectrin, α-antitrypsin, adenosine deaminase (ADA), metal transporter (ATP7A or ATP7), sulfamidase, enzymes involved in lysosomal storage disorders (ARSA), hypoxanthine guanine phosphoribosyltransferase, β-25 glucocerebrosidase, sphingomyelinase, and lysoso Hexosaminidase, branched-chain keto acid dehydrogenase, hormones, growth factors, insulin-like growth factor 1 or 2, platelet-derived growth factor, epidermal growth factor, nerve growth factor, neurotrophic factors-3 and -4, brain-derived n-eurotrophic factor, glial-derived growth factor, transforming growth factors α and β, cytokines, α-interferon, β-interferon, interferon-γ, interleukin-2, interleukin-4, interleukin-12, granulocyte-macrophage colony-stimulating factor, lymphotoxin, suicide gene product, herpes simplex virus thymidine kinase, cytosine deaminase, diphtheria toxin, cytochrome P450, deoxycytidine kinase, tumor necrosis factor, drug resistance proteins, tumor suppressor proteins (e.g., p53, Rb, Wt-1, NF1, Von) Hippel-Lindau (VHL), adenomatous polyposis (APC), immunomodulatory peptides, tolerogenic or immunogenic peptides or proteins Tregitope or hCDR1, insulin, glucokinase, guanylate cyclase 2D (LCA-GUCY2D), Rab escort protein 1 (choroidemia), LCA 5 (LCA-level cyclin), ornithine keto acid aminotransferase (gyrate atrophy), retinosuxin 1 (X-linked retinoschisis), USH1C (Usher syndrome 1C), X-linked retinitis pigmentosa GTPase (XLRP), MERTK (AR-type RP: retinitis pigmentosa), DThe method according to any one of claims 1 or 3 to 53, comprising encoding FNB1 (connexin 26 hearing loss), ACHM 2, 3 and 4 (color blindness), PKD-1 or PKD-2 (polycystic kidney disease), TPP1, CLN2, sulfatase, N-acetylglucosamine-1-phosphate transferase, cathepsin A, GM2-AP, NPC1, VPC2, sphingolipid-activated protein, one or more zinc finger nucleases for genome editing, and one or more donor sequences used as repair templates for genome editing.

57. The method according to any one of claims 2, 4 to 49, wherein the heterogeneous polynucleotide encodes an inhibitory nucleic acid.

58. The method according to claim 57, wherein the inhibitory nucleic acid is selected from the group consisting of siRNA, antisense molecules, miRNA, RNAi, ribozymes, and shRNA.

59. The inhibitory nucleic acids include the huntingtin (HTT) gene, genes associated with dentate lepidopteran atrophy (atrophin 1, ATN1), the X-chromosome androgen receptor for spinal medullary muscle atrophy, human ataxin-1, -2, -3, and -7, Cav2.1P / Q voltage-gated calcium channel (CACNA1A), TATA-binding protein, ataxin 8 counter-chain (ATXN8OS), and serine / threonine protein phosphatase 2A 55kDa regulatory subunit B beta isoforms (types 1, 2, 3, 6, 7, 8, 12) in spinocerebellar ataxia. 17) FMR1 (Fragile X Intellectual Disability 1) in Fragile X Syndrome, FMR1 (Fragile X Intellectual Disability 1) in Fragile X-Associated Tremor / Ataxia Syndrome, FMR1 (Fragile X Intellectual Disability 2) in Fragile XE, or AF4 / FMR2 Family Member 2 Intellectual Disability; Myotonin Protein Kinase (MT-PK) in Myotonic Dystrophy; Frataxin in Friedreich's Ataxia; Variants of the Superoxide Dismutase 1 (SOD1) Gene in Amyotrophic Lateral Sclerosis; Genes involved in the pathogenesis of Parkinson's Disease and / or Alzheimer's Disease, Apolipoprotein B (APOB) and Proprotein Convertase Subtilisin / Kexin 9 (PCSK9), Hypercholesterolemia; HIVTat, a human immunodeficiency virus transactivator of transcription genes in HIV infection; HIVTAR in HIV infection. TAR, human immunodeficiency virus transactivator response element gene, C-C chemokine receptor (CCR5) in HIV infection, Roussarcoma virus (RSV) nucleocapsid protein in RSV infection, liver-specific microRNA (miR-122) in hepatitis C virus infection, p53, acute kidney injury or delayed kidney transplantation or kidney injury; protein kinase N3 (PKN3) in advanced, recurrent, or metastatic solid malignancies; LMP2, also known as proteasome subunit beta type 9 (PSMB 9), metastatic melanoma; LMP7, also known as proteasome subunit beta type 8 (PSMB 8), metastatic melanoma; MECL1, also known as proteasome subunit beta type 10 (PSMB 10), metastatic melanoma; vascular endothelial growth factor (VEGF) in solid tumors;Kinesin spindle protein in solid tumors; apoptosis inhibitor B-cell CLL / lymphoma (BCL-2) in chronic myeloid leukemia; ribonucleotide reductase M2 (RRM2) in solid tumors; furin in solid tumors; polo-like kinase 1 (PLK1) in liver tumors; diacylglycerol acyltransferase 1 (DGAT1) in hepatitis C infection; beta-catenin in familial adenomatous polyposis; beta-2 adrenergic receptor; glaucoma; RTP801 / Redd1, also known as DNA damage-induced transcript 4 protein, in diabetic macular edema (DME) or age-related macular degeneration; vascular endothelial growth factor receptor I (VEGFR1) in age-related macular degeneration or choroidal angiogenesis. ), caspase 2 in non-arteritic ischemic optic neuropathy; keratin 6AN17K mutant protein in congenital thick dura mater; genome / gene sequence of influenza A virus in influenza infection; genome / gene sequence of severe acute respiratory syndrome (SARS) coronavirus in SARS infection; genome / gene sequence of respiratory syncytial virus in respiratory syncytial virus infection; genome / gene sequence of Ebola filovirus in Ebola infection; genome / gene sequence of hepatitis B and C viruses in hepatitis B and C infection; genome / gene sequence of herpes simplex virus (HSV) in HSV infection; genome / gene sequence of coxsackievirus B3 in coxsackievirus B3 infection. The method according to claim 57, relating to a gene, gene transcript, or binding to a gene transcript, in connection with a polynucleotide repetition disorder selected from the group consisting of tolsin A (TOR1A), pan-class I, and transplant-specific HLA alleles in primary dystonia; and mutant rhodopsin gene (RHO) in autosomal dominant retinitis pigmentosa (adRP).

60. The method according to any one of claims 1, 3, and 5 to 59, wherein the protein encoded by heterologous polynucleotides comprises a gene editing nuclease.

61. The method according to claim 60, wherein the gene editing nuclease comprises a zinc finger nuclease (ZFN) or a transcription activator-like effector nuclease (TALEN).

62. The method according to claim 61, wherein the gene editing nuclease comprises a functional type II CRISPR-Cas9.

63. The method according to any one of claims 1 to 62, wherein step (a) and / or step (b) are performed two or more times.

64. The method according to any one of claims 1 to 63, wherein the subject is a human.

65. (a) Recombinant viral vectors containing heterologous polynucleotides encoding proteins or peptides; (b) Proteases or glycosidases that break down or digest antibodies, and (c) A label containing instructions for carrying out the method according to any one of claims 1 to 64, wherein (a) and (b) are in separate or the same container. A package that contains [something] inside.

66. (a) Recombinant viral vectors containing heterologous polynucleotides transcribed into nucleic acids that inhibit, reduce, or decrease protein expression; (b) Proteases or glycosidases that break down or digest antibodies, and (c) A label containing instructions for carrying out the method according to any one of claims 1 to 64, wherein (a) and (b) are in separate or the same container. A package that contains [something] inside.

67. Immunoglobulin G-degrading enzyme polypeptide for use in the treatment of diseases treated by gene therapy vectors in patients who require it.

68. The immunoglobulin G-degrading enzyme polypeptide for use according to claim 67, wherein the vector is an adeno-associated virus (AAV) vector, a lentiviral vector, or an adenovirus vector.

69. The immunoglobulin G-degrading enzyme polypeptide for use according to claim 68, wherein the vector is an AAV vector comprising a capsid protein selected from the group consisting of AAV1, AAV2, AAV2 variant, AAV3, AAV3 variant, AAV3B, AAV3B variant, AAV4, AAV5, AAV6, AAV6 variant, AAV7, AAV8, AAV9, AAV10, AAVcy10, AAVrh10, AAVrh74, AAVdj, AAV-Anc80, SEQ ID NO: 1, SEQ ID NO: 2, or AAV2i8.

70. The immunoglobulin G-degrading enzyme polypeptide for use according to claims 67 to 69, wherein the immunoglobulin G-degrading enzyme polypeptide comprises one sequence of SEQ ID NOs: 3-18, 23, or 48.

71. The immunoglobulin G-degrading enzyme polypeptide for use according to claim 70, further comprising one non-natural signal sequence from SEQ ID NOs: 49 to 51.

72. Diseases treated by gene therapy vectors include proliferative disorders (cancer, tumors, dysplasia, etc.), Krigler-Najjar and Krigler-Najjar hepatic metabolic disorders, Friedreich's ataxia, infections, intoxication (e.g., tobacco, alcohol, or drugs), epilepsy, Canavan disease, adrenoleukodystrophy, viral diseases (e.g., hepatitis B or C virus, HIV-induced), herpes, retroviruses, etc. , hereditary disorders (myopathy such as cystic fibrosis, dystroglycanopathy, Duchenne myopathy or dystrophy, myotubular myopathy, hemophilia A, hemophilia B, sickle cell anemia, sickle cell disease, Fanconi anemia, diabetes mellitus, amyotrophic lateral sclerosis (ALS), myotubular myopathy, motor neuron diseases such as spinal muscular atrophy (SMA), spinal medullary muscular atrophy, or Charcott-Marie-dental disease, arthritis, severe combinations Immunoglobulin G-degrading enzyme polypeptides for use according to claims 67 to 71, selected from the group consisting of immunodeficiency disorders (RS-SCID, ADA-SCID, X-SCID, etc.), Wiscott-Aldrich syndrome, X-linked thrombocytopenia, X-linked congenital neutropenia, chronic granulomatous disease, etc.), coagulation factor deficiencies, cardiovascular diseases (retinitis pigmentosa), ischemia, dyslipidemia, homozygous familial hypercholesterolemia, etc.), eye diseases such as retinitis pigmentosa, Lieber congenital amaurosis, Lieber hereditary optic neuropathy, Stargardt disease, etc.; lysosomal storage disorders such as Sanfilippo syndrome; hyperbilirubinemia or Gilbert syndrome such as CN type I or II; glycogen storage disorders such as Fabry disease, GSDI, GSDII (Pompe disease), GSDIII, GSDIV, GSDV, GSDVI, GSDVII, GSDVIII, and fatal congenital glycogen storage disorders of the heart.

73. The immunoglobulin G-degrading polypeptide for use according to claims 67-72, wherein the vector comprises a therapeutic polynucleotide suitable for treating the disease described in claim 72.

74. A nucleic acid sequence encoding an immunoglobulin G-degrading enzyme polypeptide for use in treating diseases treated by gene therapy vectors in patients who require it.

75. An expression vector comprising a nucleic acid sequence encoding an immunoglobulin G-degrading enzyme polypeptide for use in treating diseases treated by gene therapy vectors in patients who require it.

76. A therapeutic composition for use in the treatment of a disease treated by a gene therapy vector for a patient in need thereof, comprising an immunoglobulin G-degrading enzyme polypeptide comprising any sequence of SEQ ID NOs: 3-18, 23, or 48; a nucleic acid sequence encoding an immunoglobulin G-degrading enzyme polypeptide comprising any sequence of SEQ ID NOs: 3-18, 23, or 48; or an expression vector comprising a nucleic acid sequence encoding an immunoglobulin G-degrading enzyme polypeptide comprising any sequence of SEQ ID NOs: 3-18, 23, or 48.

77. A method for treating a disease treated by a gene therapy vector, comprising administering a therapeutically effective amount of immunoglobulin G-degrading enzyme polypeptide to a subject in need thereof.

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