Journal of Genetic Syndromes & Gene Therapy
Open Access

Tailored inhibition of cystine stone formation as a therapy for cystinuria

Annual Congress on Rare Diseases & Orphan Drugs

October 26-27, 2016 Chicago, USA

Sahota A, Yang M, Goldfarb D S, Ward M D and Tischfield J A

Rutgers University, USA
NYU Langone Medical Center, USA
New York University, USA

Scientific Tracks Abstracts: J Genet Syndr Gene Ther

Abstract :

Background & Aim: Cystinuria, caused by mutations in SLC3A1 or SLC7A9 is characterized by excessive excretion of cystine in the urine and cystine stones in the urinary tract. Cystine stones are difficult to treat surgically and medical treatments have major side effects. Previous studies from our group have demonstrated that cystine analogs such as cystine dimethyl ester (CDME) inhibit cystine crystallization in vitro. Here we show that this analog also inhibits cystine stone formation in Slc3a1 knockout mice. Methods: CDME (200 �?¼g per mouse) or water was administered by stomach tube daily for four weeks; higher doses were administered to assess organ toxicity. Urinary amino acids and cystine stones were analyzed to assess drug efficacy using several analytical techniques. Results: Treatment with CDME led to a significant decrease in stone size compared with the water group (p=0.0002), but the number of stones was greater (p=0.005). The change in stone size distribution between the two groups was evident by micro computed tomography. Scanning electron microscopy analysis of cystine stones from the CDME group demonstrated a change in crystal habit with numerous small crystals. L-cysteine methyl ester was detected by UPLC-MS in stones from the CDME group only, indicating that CDME is absorbed from the intestine and a metabolic product incorporated into the stone material. No pathological changes were observed at the doses tested. Conclusions: These data demonstrate that CDME promotes formation of small stones but does not prevent stone formation, consistent with the hypothesis that CDME inhibits cystine crystal growth. Combined with the lack of observed adverse effects, our findings support the use of CDME as a viable treatment for cystine urolithiasis.

Biography :

Sahota A is a Professor in the Department of Genetics, Director of Scientific Programs and Director of the Clinical Genomics Laboratory, RUCDR Infinite Biologics; Clinical Professor and Laboratory Director in the Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School (RWJMS) and Clinical Professor in the Division of Urology, RWJMS.

Email: Sahota@dls.rutgers.edu