Brian Bigger Research Group

Research interests

The 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 licencing 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 projects

• Treating Herpes Simplex Virus encephalitis using gene therapy to deliver inflammatory modulators
• Developing improved stem cell gene therapy treatments for Hunter disease and Sanfilippo disease type B
• New 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 Members

• Dr Emily Miedzybrodzka – Research Project manager
• Dr Shaun Wood – Research Fellow
• Advert live – Research Fellow
• TBC - Research Fellow
• Ms Yuko Ishikawa Learmonth - Research Assistant
• Ms Rachel Searle - PhD Student

Selected recent publications

Ellison 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. Accepted

Wu 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 feature

Wood 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 feature

Ellison 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;31:101127

O'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):437

Ellison S, Parker H, Bigger B. Advances in therapies for neurological lysosomal storage disorders. J Inherit Metab Dis. 2023 Review

Mandolfo 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. Review

Mandolfo 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):e11185

Collaborators

• Centre Hospitalier Universitaire Sainte-Justine - Alexey Pshezhetsky
• Defence Science and Technology Laboratory - Stephanie Southern, Riccardo D’Elia
• Kings College London - Farzin Farzeneh, Lucas Chan, Els Henckearts
• Lincoln University - Nadia Mitchell, Dave Palmer
• Manchester University NHS Foundation Trust - Simon Jones, Rob Wynn, Teresa Wu
• Nemours Health – Shunji Tomatsu
• Orchard Therapeutics
• Paracelsus Medical University – Anna Wiesinger, Florian Lagler
• University College London  - Adrian Thrasher, Claire Booth, Karen Buckland
• University of Liverpool – Benedict Michael
• University of Manchester – Perdi Barran, Herve Boutin, David Brough

Funders

Defence Science and Technology Laboratory

Great Ormond Street Hospital charity

BBSRC

The UK Society for Mucopolysaccharide Diseases

Cure Sanfilippo Foundation