Bloomsbury Genetic Therapies Announces Recent Publication of Three Articles Supporting the Preclinical Efficacy and Differentiation of BGT-OTCD as a Potential Treatment for Ornithine Transcarbamylase Deficiency (OTCD)

London, UK, 18 September 2023 – Bloomsbury Genetic Therapies Limited, a clinical-stage biotechnology company developing potentially curative treatments for patients suffering from rare neurological and metabolic diseases based on clinically proven gene therapy technologies, announced today the recent publication of three research articles supporting the preclinical efficacy and differentiation of BGT-OTCD as a potentially curative solution for ornithine transcarbamylase deficiency (OTCD) patients following a one-time intravenous injection.

These publications outline the latest extensive research works on the optimization and characterization of liver-targeted AAVs initiated over a decade ago by our collaborators at Children's Medical Research Institute (CMRI), Sydney Children's Hospitals Network (SCHN) and the University of Sydney. Professor Ian Alexander, Head of the Gene Therapy Research Unit at CMRI and SCHN, designed and led the early development of BGT-OTCD in collaboration with Dr Sharon Cunningham and Associate Professor Leszek Lisowski from CMRI.

• “Harnessing the power of whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation” by Cabanes-Creus M, Sophia H.Y. Liao, Renina Gale Navarro, et al., pre-published on bioRxiv in July 2023 and available online via this link demonstrates the superiority of BGT-OTCD’s capsid, AAV-LK03, at transducing hepatocytes and driving transgene expression in a human liver explant model  compared to other capsids such as AAV8, AAV5 or AAV9, commonly used in other liver-targeted gene therapy drug candidates. Transduction and expression with an AAV-LK03 capsid were shown to be up to 24 times and 85 times higher, respectively, than with an AAV8 capsid, for instance.
• “Characterization of the humanized FRG mouse model and development of an AAV-LK03 variant with improved liver lobular biodistribution” by Cabanes-Creus M, Navarro RG, Liao SHY, et al., published in Molecular Therapy – Methods & Clinical Development in January 2023 and available online via this link further elucidates the preferential affinity of the AAV-LK03 capsid to periportal hepatocytes compared to other capsids such as AAV8 or AAV9, which predominantly exhibit an affinity for perivenous hepatocytes. Since the urea cycle primarily takes place in the periportal hepatocytes and ornithine transcarbamylase is an intracellular enzyme, thereby offering very limited potential for a cross-correction from perivenous hepatocytes’ expression to periportal hepatocytes, preferential targeting of periportal hepatocytes is expected to be a significant efficacy driver for BGT-OTCD compared to other OTCD AAV gene therapy programs relying on capsids such as AAV8.
• “Recapitulation of skewed X-inactivation in female OTC-deficient primary human hepatocytes in the FRG mouse: a novel system for developing epigenetic therapies” by Cunningham SC, van Dijk EB, Zhu E, et al., published in Human Gene Therapy in June 2023 and available online via this link, summarizes the compelling efficacy data obtained with BGT-OTCD in the FRG mouse model, of high translational relevance, via normalization of orotic aciduria.

“Collectively these data provide a compelling case for the use of AAV-LK03 in liver-targeted gene therapy applications such as OTCD, and I look forward to seeing exciting therapeutic impact in the imminent HORACE trial”, said Professor Ian Alexander.

The U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) recently approved the clinical trial application (CTA) submitted by Bloomsbury’s collaborators at University College London (UCL) for HORACE (Halting Ornithine transcarbamylase deficiency with Recombinant AAV in ChildrEn; NCT 05092685), a phase 1/2 clinical trial of BGT-OTCD in paediatric patients diagnosed with OTCD to be initiated in Q4 2023.