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conferenceseries.com
October 26-27, 2016 Chicago, USA
Annual Congress on
Rare Diseases & Orphan Drugs
Volume 7, Issue 5 (Suppl) J Genet Syndr Gene Ther
ISSN: 2157-7412 JGSGT, an open access journal Rare Diseases 2016
October 26-27, 2016
Tailored inhibition of cystine stone formation as a therapy for cystinuria
Sahota A1, Yang M1, Goldfarb D S2, Ward M D3 and Tischfield J A1
1Rutgers University, USA
2NYU Langone Medical Center, USA
3New York University, USA
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 μg 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.
Sahota A et al., J Genet Syndr Gene Ther 2016, 7:5 (Suppl)