Mr NIRMAL BHATT1,2, Mr CONNOR ANDERSON1,3, Miss THERESA NGUYEN1, Mr GABRIEL RODRIGUEZ1, Dr GAETAN BURGIO4, Dr SIMON JIANG4,5,6, Dr ANIRUDDH DESHPANDE2,7,8, Dr MALCOLM STARKEY1,2
1Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Australia , 2Priority Research Centre GrowUpWell, The Faculty of Health and Medicine and Hunter Medical Research Institute, The University of Newcastle, Newcastle, Australia, 3Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Australia, 4Department of Immunology and Infectious Diseases, Australian National University, Canberra , Australia, 5Centre for Personalized Immunology, John Curtin School of Medical Research, Australian National University, Canberra , Australia, 6Department of Nephrology, The Canberra Hospital, Canberra , Australia, 7Centre for Kidney Research, Children’s Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia , Sydney, Australia, 8Urology Unit, Department of Surgery, Children’s Hospital at Westmead, Sydney, Australia
Aim: To evaluate the effect of alpha-lipoic acid (α-LA) in a personalised model of type II cystinuria.
Background: Cystinuria is an inheritable genetic disorder characterized by the accumulation of cystine in the urine. Cystinuria accounts for 1-2% of all adult kidney stones and 3-10% in children. Type II cystinuria is caused by mutations in the SLC7A9 gene that is primarily expressed in the proximal tubules. To test the effectiveness of therapeutics in cystinuria, cystine transporter gene deficient (-/-) mice have been developed. However, these models do not represent the clinical situation, where point mutations cause cystinuria. As cystinuria is a rare disease, running clinical trials is challenging. Therefore, creating personalised models of clinically relevant point mutations may afford individualised approaches. α-LA has been shown to be an effective treatment in an experimental gene-deficient mouse model of type I cystinuria and has entered clinical trials. We sought to test α-LA in a personalised model of type II cystinuria.
Methods: We have identified a pathogenic mutation in a severe early-onset paediatric case of cystinuria classified as SLC7A9G105R. We generated Slc7a9G105R mutant mice using CRISPR/Cas9 technology. We then tested the efficacy of α-LA dietary supplementation in reducing cystine stone formation using computed tomographic (µ-CT) imaging.
Results: 100% of male Slc7a9G105R mutant mice developed cystine stones by 9-weeks. α-LA treatment significantly reduced stone number, volume, and weight with 80% of α-LA-treated mice presenting with no stones.
Conclusions: Our findings prove that the development of translational personalised models of monogenic kidney stone diseases are feasible, and that α-LA is effective in preventing type II cystinuria. The crucial next step is to take α-LA into broader clinical trials, including in paediatrics.
Biography:
I completed my master’s studies from Kangwon National University, Republic of Korea. My research project was entitled ‘Apocynin attenuates LPS-induced mesangial cell damage’. After completion of my master’s degree, I made significant contributions to research projects related to respiratory complications including asthma, COPD and sepsis using in vitro and in vivo experimental models in my capacity as a research assistant at Chonbuk National University Medical School, Republic of Korea. Prior to this, I was used in undergraduate research projects and completed mini-thesis. Currently, I am PhD at Monash Univeristy and involving in various in vivo kidney stone disease research projects.