Developing stem cell gene therapies for childhood dementias and multisystem diseases Professor Brian Bigger Chair of Advanced Therapeutics Centre for Regenerative Medicine Institute for Regeneration and Repair Contact details Email: brian.bigger@ed.ac.uk Research interestsThe Bigger lab is focussed on developing gene and stem cell therapies for patients with chronic diseases.As such, we have developed several lentiviral based ex vivo haematopoietic stem cell gene therapies for lysosomal storage disorders, many of which are childhood dementias and taken these through to clinical trials in patients and licensing to companies, including the cofounding of Orchard Therapeutics. In future we will focus on improving the toxic conditioning required to deliver these therapies and other cell based delivery approaches for delivering gene therapy.We have also developed Adeno-Associated Viral vectors for childhood dementias and are focussed on how we can improve existing gene therapy vector systems including through the use of specific promoters and peptide tagging to drive expression towards specific organ systems.Lastly, neuroinflammation and the modulation of neuroinflammation in multiple disease settings using gene therapy has been a focus of the lab for many years.Key projectsTreating Herpes Simplex Virus encephalitis using gene therapy to deliver inflammatory modulatorsDeveloping improved stem cell gene therapy treatments for Hunter disease and Sanfilippo disease type BNew Mass Spectrometry Methods to Characterise Virus Based Drug Products (Collaboration with University of Manchester)Clinical trials of ex vivo HSC gene therapy in Sanfilippo disease and Hunter disease (Collaboration with University of Manchester)Group MembersDr Emily Miedzybrodzka – Research Project ManagerDr Shaun Wood – Research FellowDr Bei Qiu – Research FellowYuko Ishikawa Learmonth - Research AssistantRachel Searle - PhD StudentMary Lorino - PhD StudentSelected recent publicationsEllison SE, Bigger BW. Design and validation of a GMP stem cell manufacturing protocol for MPSII hematopoietic stem cell gene therapy Mol Ther Methods Clin Dev. AcceptedWu THY, Brown HA, Church HJ, Kershaw CJ, Hutton R, Egerton C, Cooper J, Tylee K, Cohen RN, Gokhale D, Ram D, Morton G, Henderson M, Bigger BW, Jones SA. Improving newborn screening test performance for metachromatic leukodystrophy: Recommendation from a pre-pilot study that identified a late-infantile case for treatment. Mol Genet Metab. 2024 May;142(1):108349.Mandolfo O, Liao A, Singh E, O'leary C, Holley RJ, Bigger BW. Establishment of the Effectiveness of Early Versus Late Stem Cell Gene Therapy in Mucopolysaccharidosis II for Treating Central Versus Peripheral Disease. Hum Gene Ther. 2024 Apr;35(7-8):243-255. * Cover featureWood SR, Chaudrhy A, Ellison S, Searle R, Burgod C, Tehseen G, Forte G, O'Leary C, Gleitz H, Liao A, Cook J, Holley R, Bigger BW. Fusion of Rabies Virus Glycoprotein or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II. Hum Gene Ther. 2024 Apr;35(7-8):232-242. * Cover featureEllison S, Liao A, Gleitz HFE, Parker H, Booth L, Robinson J, Wood S, Taylor J, Holley R, Bigger BW. Sustained long-term disease correction in a murine model of MPSII following stem cell gene therapy. Mol Ther Methods Clin Dev. 2023 Oct 20;31:101127O'Leary C, Forte G, Mitchell NL, Youshani AS, Dyer A, Wellby MP, Russell KN, Murray SJ, Jolinon N, Jones SA, Stacey K, Davis DM, Henckaerts E, Palmer DN, Kamaly-Asl I, Bigger BW. Intraparenchymal convection enhanced delivery of AAV in sheep to treat Mucopolysaccharidosis IIIC. J Transl Med. 2023 Jul 5;21(1):437Ellison S, Parker H, Bigger B. Advances in therapies for neurological lysosomal storage disorders. J Inherit Metab Dis. 2023 ReviewMandolfo O, Bigger B.W. Gene-modified neural progenitor cells for the treatment of neuropathic lysosomal storage diseases. Neural Regen. Res. 2023 Jan 30;18 (9),1954-5. ReviewMandolfo O, Parker H, Bigger B. Innate Immunity in Mucopolysaccharide diseases. Int. J. Mol. Sci. 2022 Feb 11;23(4):1999. Review.Taylor JT, Ellison S, Pandele A, Wood S, Nathan E, Forte G, Parker H, Zindy E, Elvin M, Dickson A, Williams KJ, Karabatsou K, McCabe M, McBain C, Bigger BW. Actinomycin D Downregulates Sox2 and Improves Survival in Preclinical Models of Recurrent Glioblastoma. Neuro Oncol. 2020 Sep 29;22(9):1289-1301.Parker H, Ellison SM, Holley RJ, O'Leary C, Liao A, Asadi J, Glover E, Ghosh A, Jones S, Wilkinson FL, Brough D, Pinteaux E, Boutin H, Bigger BW. Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA. EMBO Mol. Med. 2020 Mar 6;12(3):e11185CollaboratorsCentre Hospitalier Universitaire Sainte-Justine - Alexey PshezhetskyDefence Science and Technology Laboratory - Stephanie Southern, Riccardo D’EliaKings College London - Farzin Farzeneh, Lucas Chan, Els HenckeartsLincoln University - Nadia Mitchell, Dave PalmerManchester University NHS Foundation Trust - Simon Jones, Rob Wynn, Teresa WuNemours Health – Shunji TomatsuOrchard TherapeuticsParacelsus Medical University – Anna Wiesinger, Florian LaglerUniversity College London - Adrian Thrasher, Claire Booth, Karen BucklandUniversity of Liverpool – Benedict MichaelUniversity of Manchester – Perdi Barran, Herve Boutin, David BroughFundersDefence Science and Technology LaboratoryGreat Ormond Street Hospital charityBBSRCThe UK Society for Mucopolysaccharide DiseasesCure Sanfilippo Foundation This article was published on 2024-05-23