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Prof Amit Nathwani

  • Telephone:

    2076796225

  • Extension:

    46225

  • Fax:

    2076796222

  • Email:

    amit.nathwani@ucl.ac.uk

  • Address:

    UCL Cancer Institute, Paul O'Gorman Building,
    72 Huntley Street,
    London,
    WC1E 6BT

  • Appointments:

    , Research Department of Haematology, Cancer Institute

Research Summary

The main thrust of my research is the development of novel treatment avenues for haematological disorders and cancer using the gene transfer technology. I am in addition interested in stem cell biology
My group has developed a distinctive approach for gene therapy of haemophilia B using a self complementary adeno-associated viral vector (AAV), in collaboration with St Jude Children's Research Hospital in Memphis Tennessee. This vector is significantly more potent than conventional AAV vectors. We have demonstrated the preclinical safety and efficacy of this new vector system and are about to commence a Phase I/II study in subjects with severe haemophilia B. Other clinical targets that are currently being evaluated include: Haemophilia A, Congenital FVII and FX deficiency, urea cycle and lysosomal storage disorders.
Haemato-oncology research is focused on the development of two emerging strategies: immunotherapy and anti-angiogenesis. Gene-therapy approaches are central to each of these strategies. Immunotherapy strategies using engineered T cells are being evaluated for the treatment of chronic lymphocytic leukaemia, a disease that remains incurable. Angiogenesis is required for the growth of tumours including haematological malignancies thus making it an important target for anti-cancer strategies. Long-term expression of an angiogenesis inhibitor is likely to be required and the role of gene therapy-mediated delivery of these agents is being evaluated.
Recently we have begun a program of research on reprogramming of somatic cells and the role of transcription factors on haematopoietic differentiation of embryonic stems cells.
Gene therapy for haematological malignancies: My haemato-oncology research is focused on the development of two emerging strategies: immunotherapy and anti-angiogenesis. Gene-therapy approaches are central to each of these strategies.

Immunotherapy strategies are directed against chronic lymphocytic leukaemia, a disease that remains incurable. Current emphasis is on the adoptive transfer of bi-specific gene modified T cells which recognise CMV infected cells through their native receptor and CLL via a tumour antigen specific receptor. Our ultimate goal is to adoptively transfer bi-specific cells immediately after front line therapy in patients with poor prognosis CLL.
Angiogenesis is required for the growth of tumours including haematological malignancies thus making it an important target for anti-cancer strategies. Long-term expression of an angiogenesis inhibitor is likely to be required for the successful treatment of malignancies. Therefore, gene therapy-mediated delivery of these agents is an alternative way to provide long-term expression of these therapeutic proteins. Vectors expressing a number of different angiogenesis inhibitors are currently being designed and tested in vitro and in vivo in murine models of leukaemia and lymphoma.

Research Activities

  • Application of liver cell biology to developing ne
  • Clinical, genetic and cell biology studies of hereditary movement disorders: dystonia, Huntington’s disease, Hereditary spastic paraplegia
  • Gene therapy for haematological disorders
  • Gene- and oligonucleotide-based therapies
  • Inhibition of angiogenesis
  • stem cell biology

Recent Publications

Displaying 50 most recent publications. For the full list please visit UCL Discovery

  1. Rahim AA,Wong AM,Ahmadi S,Hoefer K,Buckley SM,Hughes DA,Nathwani AN,Baker AH,McVey JH,Cooper JD,Waddington SN (2012) In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression. Gene Ther, 19(9), 936 - 946. 10.1038/gt.2011.157.
  2. Mattar CN,Nathwani A,Rosales C,Waddington S,Johana N,Ng X-W,Biswas A,Choolani M,Chan JKY (2012) Early AAV-Mediated Intrauterine Gene Therapy at 0.4G in Non-Human Primates MOLECULAR THERAPY, 20, S252 - S253.
  3. Sack BK,Merchant S,Markusic DM,Nathwani AC,Davidoff AM,Byrne BJ,Herzog RW (2012) Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy PLoS ONE, 7(5).
  4. McIntosh JH,Cochrane M,Cobbold S,Waldmann H,Nathwani SA,Davidoff AM,Nathwani AC (2012) Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine. Gene Ther, 19(1), 78 - 85. 10.1038/gt.2011.64.
  5. Theodoulou A,Berryman J,Nathwani A,Scully M (2012) Comparison of cryoprecipitate with fibrinogen concentrate for acquired hypofibrinogenaemia Transfusion and Apheresis Science, 46(2), 159 - 162.
  6. McIntosh JH,Cochrane M,Cobbold S,Waldmann H,Nathwani SA,Davidoff AM,Nathwani AC (2012) Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine Gene Therapy, 19(1), 78 - 85.
  7. Theodoulou A,Berryman J,Nathwani A,Scully M (2012) Comparison of cryoprecipitate with fibrinogen concentrate for acquired hypofibrinogenaemia. Transfus Apher Sci, 46(2), 159 - 162. 10.1016/j.transci.2011.11.005.
  8. Della Peruta M,Binny C,Nathwani D,McIntosh J,Rosales C,Davidoff AM,Williams R,Chokshi S,Nathwani AC (2012) DEVELOPMENT OF A LIVER-SPECIFIC, TUMOUR-SELECTIVE RECOMBINANT ADENO-ASSOCIATED VIRUS VECTOR TO TARGET HEPATOCELLULAR CARCINOMA JOURNAL OF HEPATOLOGY, 56, S111 - S111.
  9. Farren TW,Liu F,Macey MG,Jenner M,Prentice A,Nathwani A,Agrawal SG (2011) CD160: a novel approach to minimal residual disease (MRD) assessment in chronic lymphocytic leukaemia (CLL) BRITISH JOURNAL OF HAEMATOLOGY, 153, 72 - 72.
  10. Ward NJ,Buckley SM,Waddington SN,Vandendriessche T,Chuah MK,Nathwani AC,McIntosh J,Tuddenham EG,Kinnon C,Thrasher AJ,McVey JH (2011) Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood, 117(3), 798 - 807. 10.1182/blood-2010-05-282707.
  11. Raj D,Peggs K,Pule M,Linch D,Davies M,Nathwani A (2011) Adoptive immunotherapy for patients with chronic lymphocytic leukaemia using a chimeric antigen receptor targeting CD23 HUMAN GENE THERAPY, 22(10), A120 - A121.
  12. Casper CJ,Warner TT,Taanman JW,Nathwani AC (2011) Generation of iPS-derived dopaminergic neurons as an in-vitro model of Rapid-Onset Dystonia Parkinsonism HUMAN GENE THERAPY, 22(10), A42 - A43.
  13. McIntosh J,Lenting P,Tuddenham E,Nawathe S,Waddington S,Gray J,Davidoff A,Nathwani A (2011) AAV mediated Factor VIII expression from a novel expression cassette with a potent codon-optimised FVIII construct HUMAN GENE THERAPY, 22(10), A28 - A28.
  14. Mattar CN,Nathwani AC,Waddington SN,Dighe N,Kaeppel C,Nowrouzi A,McIntosh J,Johana NB,Ogden B,Fisk NM,Davidoff AM,David A,Peebles D,Valentine MB,Appelt JU,von KC,Schmidt M,Biswas A,Choolani M,Chan JK (2011) Stable Human FIX Expression After 0.9G Intrauterine Gene Transfer of Self-complementary Adeno-associated Viral Vector 5 and 8 in Macaques Mol.Ther., 19(11), 1950 - 1960. 10.1038/mt.2011.107.
  15. Fagone P,Wright JF,Nathwani AC,Nienhuis AW,Davidoff AM,Gray JT (2011) Systemic Errors in Quantitative Polymerase Chain Reaction Titration of Self-Complementary Adeno-Associated Viral Vectors and Improved Alternative Methods Hum.Gene Ther.. 10.1089/hum.2011.104.
  16. David AL,McIntosh J,Peebles DM,Cook T,Waddington S,Weisz B,Wigley V,Abi-Nader K,Boyd M,Davidoff AM,Nathwani AC (2011) Recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep. Hum Gene Ther, 22(4), 419 - 426. 10.1089/hum.2010.007.
  17. Hillmen P,Gribben JG,Follows GA,Milligan D,Sayala HA,Moreton P,Oscier DG,Dearden CE,Kennedy DB,Pettitt AR,Nathwani A,Cohen D,Rawstron A,Pocock CFE,Sub-Grp NCRICLL (2011) Final response assessment of the CLL208 trial: an open-label phase II study to investigate the safety and efficacy of rituximab plus chlorambucil in previously untreated patients with CD20-positive B-cell chronic lymphocytic leukaemia (CLL). BRITISH JOURNAL OF HAEMATOLOGY, 153, 21 - 21.
  18. Della Peruta M,Binny C,Nathwani D,Chokshi S,McIntosh J,Rosales C,Davidoff AM,Williams R,Nathwani AC (2011) The development of a tumour-selective recombinant adeno-associated virus vector to target hepatocellular carcinoma HUMAN GENE THERAPY, 22(10), A113 - A113.
  19. Rosales C,McIntosh J,Hanley J,Nathwani A,Morton C,Davidoff A (2011) A novel epigenetic modifier significantly improves recombinant adeno-associated virus vector mediated transgene expression in mice HUMAN GENE THERAPY, 22(10), A107 - A107.
  20. Nathwani A,Tuddenham EGD,Rosales C,Macintosh J,Chowdary P,Riddell A,Aghighi S,Griffioen A,Pie J,Harrington C,Glader B,Ng CYC,Kay M,Zhou J,Allay J,Coleman J,Sleep S,High K,Mingozzi F,Gray JT,Reiss UM,Nienhuis AW,Davidoff AM (2011) A Phase I/II clinical trial entailing peripheral vein administration of a novel self complementary adeno-associated viral vector encoding human FIX for Haemophilia B gene therapy HUMAN GENE THERAPY, 22(10), A20 - A20.
  21. Nathwani A,Binny CJ,McIntosh JH,Tuddenham EGD,Peruta MD,Kymalainen H,Buckley S,Waddington SN,McVey JH,Spence Y,Morton CL,Thrasher A,Gray JT,Castellino FJ,Tarantal AF,Davidoff AM (2011) AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous haemorrhage. Blood.
  22. Rahim AA,Wong AM,Ahmadi S,Hoefer K,Buckley SM,Hughes DA,Nathwani AN,Baker AH,McVey JH,Cooper JD,Waddington SN (2011) In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression Gene Ther.. 10.1038/gt.2011.157.
  23. Herzog RW,Davidoff AM,Markusic DM,Nathwani AC (2011) AAV Vector Biology in Primates: Finding the Missing Link? Mol.Ther., 19(11), 1923 - 1924. 10.1038/mt.2011.218.
  24. Raj D,Davidoff AM,Nathwani AC (2011) Self-complementary adeno-associated viral vectors for gene therapy of hemophilia B: progress and challenges. Expert Rev Hematol, 4(5), 539 - 549. 10.1586/ehm.11.48.
  25. Denbo JW,Williams RF,Orr WS,Sims TL,Ng CY,Zhou J,Spence Y,Morton CL,Nathwani AC,Duntsch C,Pfeffer LM,Davidoff AM (2011) Continuous local delivery of interferon-beta stabilizes tumor vasculature in an orthotopic glioblastoma xenograft resection model Surgery, 150(3), 497 - 504. 10.1016/j.surg.2011.07.044.
  26. McIntosh JH,Cochrane M,Cobbold S,Waldmann H,Nathwani SA,Davidoff AM,Nathwani AC (2011) Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine Gene Ther.. 10.1038/gt.2011.64.
  27. Nathwani AC,Tuddenham EGD,Rosales C,Macintosh J,Chowdary P,Riddell A,Aghighi S,Lilley P,Yee T,Griffioen A,Pie J,Harrington C,Glader B,Ng CYC,Kaye M,Zhou JF,Allay J,Coleman J,Sleep S,High K,Mingozzi F,Gray JT,Reiss UM,Nienhuis AW,Davidoff AM (2011) A phase i/ii clinical trial entailing peripheral vein administration of a novel self complementary adeno-associated viral vector encoding human fix for haemophilia b gene therapy HUMAN GENE THERAPY, 22(6), A7 - A8.
  28. Hillmen P,Gribben JG,Follows GA,Milligan D,Sayala HA,Moreton P,Oscier DG,Dearden CE,Kennedy DB,Pettitt AR,Nathwani A,Cohen D,Rawstron A,Pocock CF (2011) RITUXIMAB PLUS CHLORAMBUCIL (R-CHLORAMBUCIL) AS FIRST-LINE TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL): FINAL ANALYSIS OF AN OPEN-LABEL PHASE II STUDY ANNALS OF ONCOLOGY, 22, 123 - 123.
  29. Allay JA,Sleep S,Long S,Tillman DM,Clark R,Carney G,Fagone P,McIntosh JH,Nienhuis AW,Davidoff AM,Nathwani AC,Gray JT (2011) Good Manufacturing Practice Production of Self-Complementary Serotype 8 Adeno-Associated Viral Vector for a Hemophilia B Clinical Trial HUM GENE THER, 22(5), 595 - 604. 10.1089/hum.2010.202.
  30. Nathwani AC,Rosales C,McIntosh J,Rastegarlari G,Nathwani D,Raj D,Nawathe S,Waddington SN,Bronson R,Jackson S,Donahue RE,High KA,Mingozzi F,Ng CY,Zhou J,Spence Y,McCarville MB,Valentine M,Allay J,Coleman J,Sleep S,Gray JT,Nienhuis AW,Davidoff AM (2011) Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins Mol.Ther., 19(5), 876 - 885. 10.1038/mt.2010.274.
  31. Porakishvili N,Memon A,Vispute K,Kulikova N,Clark EA,Rai KR,Nathwani A,Damle RN,Chiorazzi N,Lydyard PM (2011) CD180 functions in activation, survival and cycling of B chronic lymphocytic leukaemia cells. Br J Haematol, 153(4), 486 - 498. 10.1111/j.1365-2141.2011.08605.x.
  32. Nathwani AC,Tuddenham EG,Rangarajan S,Rosales C,McIntosh J,Linch DC,Chowdary P,Riddell A,Pie AJ,Harrington C,O'Beirne J,Smith K,Pasi J,Glader B,Rustagi P,Ng CY,Kay MA,Zhou J,Spence Y,Morton CL,Allay J,Coleman J,Sleep S,Cunningham JM,Srivastava D,Basner-Tschakarjan E,Mingozzi F,High KA,Gray JT,Reiss UM,Nienhuis AW,Davidoff AM (2011) Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med, 365(25), 2357 - 2365. 10.1056/NEJMoa1108046.
  33. Hillmen P,Gribben JG,Follows GA,Milligan D,Sayala HA,Moreton P,Oscier DG,Dearden CE,Kennedy DB,Pettitt AR,Nathwani A,Cohen D,Rawstron A,Pocock CFE (2010) Rituximab Plus Chlorambucil In Patients with CD20-Positive B-Cell Chronic Lymphocytic Leukemia (CLL): Final Response Analysis of An Open-Label Phase II Study BLOOD, 116(21), 307 - 307.
  34. Walton JA,Lydyard PM,Nathwani A,Emery V,Akbar A,Glennie MJ,Porakishvili N (2010) Patients with B cell chronic lymphocytic leukaemia have an expanded population of CD4 perforin expressing T cells enriched for human cytomegalovirus specificity and an effector-memory phenotype. Br J Haematol, 148(2), 274 - 284. 10.1111/j.1365-2141.2009.07964.x.
  35. Porakishvili N,Lydyard P,Bremser A,Vispute K,Memon A,Kulikova N,Clarke E,Rai KR,Nathwani A,Damle RN,Chiorazzi N (2010) B-Cell Chronic Lymphocytic Leukemia (B-CLL) Cells Unresponsive to CD180 Ligation Fail to Respond to Anti-IgM Stimulation as Well BLOOD, 116(21), 1475 - 1475.
  36. Farren T,Liu FT,Stephens C,Macey M,Jenner M,Prentice A,Nathwani A,Agrawal S (2010) Inter-Laboratory Assessment of Minimal Residual Disease In Chronic Lymphocytic Leukemia-7 Evaluation of the Novel CD160FCA Assay BLOOD, 116(21), 1122 - 1123.
  37. Nathwani A (2010) Haemophilia B gene therapy study in the UK HAEMOPHILIA, 16(6), 973 - 973.
  38. Hillmen P,Gribben JG,Follows GA,Milligan DW,Sayala HA,Moreton P,Oscier D,Dearden CE,Kennedy DB,Pettitt AR,Nathwani A,Cohen D,Gregory WM,Rawstron AC,Hayward CRW,Pocock C (2010) An open-label phase II study to investigate the safety and efficacy of rituximab plus chlorambucil in previously untreated patients with CD20-positive B-cell chronic lymphocytic leukaemia (CLL): On behalf of the NCRI CLL sub-group BRITISH JOURNAL OF HAEMATOLOGY, 149, 2 - 2.
  39. Mattar CN,Nathwani AC,Dighe N,Waddington S,McIntosh J,Biswas A,Fisk N,Davidoff AM,David A,Peebles D,Nowrouzi A,Kappel C,Schmidt M,Choolani M,Chan J (2010) Late-Gestation Intravascular Delivery of Self-Complementary AAV Leads to Sustained Transgene Expression with the Possibility of Vector Integration Events in the Liver HUMAN GENE THERAPY, 21(4), 499 - 499.
  40. Tracey L,Streck CJ,Du Z,Williams RF,Pfeffer LM,Nathwani AC,Davidoff AM (2010) NF-κB activation mediates resistance to IFNΒ in MLL-rearranged acute lymphoblastic leukemia Leukemia, 24(4), 806 - 812.
  41. Sims TL,McGee M,Williams RF,Myers AL,Tracey L,Hamner JB,Ng C,Wu J,Gaber MW,McCarville B,Nathwani AC,Davidoff AM (2010) IFN-β restricts tumor growth and sensitizes alveolar rhabdomyosarcoma to ionizing radiation Molecular Cancer Therapeutics, 9(3), 761 - 771.
  42. Nathwani A,Tuddenham E,Rosales C,McIntosh J,Riddell A,Rustagi P,Glader B,Kay M,Allay J,Coleman J,Sleep S,High KA,Mingozzi F,Gray JT,Reiss UM,Nienhuis AW,Davidoff A (2010) Early Clinical Trial Results Following Administration of a Low Dose of a Novel Self Complementary Adeno-Associated Viral Vector Encoding Human Factor IX In Two Subjects with Severe Hemophilia B BLOOD, 116(21), 114 - 114.
  43. Nathwani AC,Tuddenham EGD,Rosales C,McIntosh J,Riddell A,Rustagi P,Galder B,Kay M,Allay J,Coleman J,Sleep S,High KA,Mingozzi F,Gray J,Reiss U,Nienhuis AW,Davidoff AM (2010) Early clinical trial results following administration of a low dose of a novel self complementary adenohyphen;associated viral vector encoding human factor ix in two subjects with severe Haemophilia B HUMAN GENE THERAPY, 21(10), 1362 - 1362.
  44. Hillmen P,Gribben JG,Follows GA,Milligan D,Sayala HA,Moreton P,Oscier DG,Deanden CE,Kennedy DB,Pettitt AR,Nathwani A,Cohen D,Rawstron A,Pocock CFE (2010) Rituximab Plus Chlorambucil In Patients with CD20-Positive B Cell Chronic Lymphocytic Leukemia (CLL) Final Response Analysis of An Open Label Phase H Study BLOOD, 116(21), 307 - 307.
  45. Nathwani A,Tuddenham E,Rosales C,McIntosh J,Riddell A,Rustagi P,Glader B,Kay M,Allay J,Coleman J,Sleep S,High KA,Mingozzi F,Gray JT,Reiss UM,Nienhuis AW,Davidoff A (2010) Early Clinical Trial Results Following Administration of a Low Dose of a Novel Self Complementary Adeno Associated Viral Vector Encoding Human Factor IX In Two Subjects with Severe Hemophilia B BLOOD, 116(21), 114 - 114.
  46. McIntosh J,Lenting PJ,Tuddenham E,Sotannde M,Waddington S,Gray JT,Davidoff A,Nathwani A (2010) Stable High Level Coagulation Factor VIII Expression In Vivo Following Gene Transfer Using a Novel Expression Cassette Encoding a More Potent FVIII Variant BLOOD, 116(21), 115 - 115.
  47. Binny CJ,McIntosh JH,Tuddenham E,Waddington S,Buckley S,Thrasher A,Gray JT,Nathwani A,Tarantal AF,Davidoff A (2010) Assessing the Potential of Perinatal Gene Transfer Using Congenital Factor VII Deficiency as a Model System BLOOD, 116(21), 114 - 114.
  48. Porakishvili N,Lydyard P,Bremser A,Vispute K,Memon A,Kulikova N,Clarke E,Rai KR,Nathwani A,Damle RN,Chiorazzi N (2010) B Cell Chronic Lymphocytic Leukemia (B CLL) Cells Unresponsive to CD180 Ligation Fail to Respond to Anti IgM Stimulation as Well BLOOD, 116(21), 1475 - 1475.
  49. Binny CJ,McIntosh JH,Tuddenham E,Waddington S,Buckley S,Thrasher A,Gray JT,Nathwani A,Tarantal AF,Davidoff A (2010) Assessing the Potential of Perinatal Gene Transfer Using Congenital Factor VII Deficiency as a Model System BLOOD, 116(21), 114 - 114.
  50. McIntosh J,Lenting PJ,Tuddenham E,Sotannde M,Waddington S,Gray JT,Davidoff A,Nathwani A (2010) Stable High Level Coagulation Factor VIII Expression In Vivo Following Gene Transfer Using a Novel Expression Cassette Encoding a More Potent FVIII Variant BLOOD, 116(21), 115 - 115.

Qualifications

  • 1997: Doctor of Philosophy, Open University
  • 1988: Member of the Royal College of Physicians, Royal College of Physicians
  • 1984: Bachelor of Medicine/Bachelor of Surgery, University of Aberdeen