Kidney Week

Abstract: SA-PO578

Development of DCR-PHXC, an Optimal Treatment Approach for Primary Hyperoxalurias

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Lai, Chengjung, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Chengjung Lai,

• Pursell, Natalie, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Natalie Pursell,

• Zhou, Wei, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Wei Zhou,

• Dills, Michael D, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Michael D Dills,

• Dutta, Chaitali, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Chaitali Dutta,

• Saxena, Utsav H, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Utsav H Saxena,

• Chopda, Girish R, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Girish R Chopda,

• Koser, Martin L, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Martin L Koser,

• Lescarbeau, Rebecca, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Rebecca Lescarbeau,

• Nazef, Naim, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Naim Nazef,

• Kim, Boyoung, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Boyoung Kim,

• Storr, Rachel A, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Rachel A Storr,

• Wang, Weimin, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Weimin Wang,

• Abrams, Marc, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Marc Abrams,

• Dudek, Hank, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Hank Dudek,

• Salido, Eduardo C., Hospital Universitario Canarias, La Laguna, Tenerife, Spain

Eduardo C. Salido,

• Brown, Bob D, Dicerna Pharmaceuticals, Inc., Cambridge, Massachusetts, United States

Bob D Brown,

Background

Primary hyperoxalurias (PHs) are autosomal recessive disorders caused by the overproduction of oxalate leading to calcium oxalate precipitation in the kidney and eventually to end stage renal disease. Currently, the only treatment effective in reducing oxalate production in patients who do not respond to high-dose vitamin B6 therapy is a combined liver and kidney transplant. We have previously demonstrated that a potential strategy to treat PH Type I (PH1), the most severe form of PH, is to reduce the hepatic production of oxalate using an RNA interference (RNAi) approach targeting hydroxyacid oxidase 1, which encodes glycolate oxidase (GO). Reduction of GO in the livers of mice and non-human primates blocks the conversion of glycolate to glyoxylate, the main precursor to oxalate in the liver. Alternatively, reducing the amount of hepatic lactate dehydrogenase (LDH) expression, the key enzyme responsible for converting glyoxylate to oxalate, should more effectively prevent the accumulation of oxalate in PH1, as well as PH Type 2, PH Type 3, and Idiopathic PH, patients.

Methods

Here we report the development of DCR-PHXC, an investigative RNAi therapeutic targeting hepatic LDH, for the treatment of PHs. DCR-PHXC was administered via subcutaneous injection to genetically engineered and chemically-induced mouse and non-human primate models of multiple PHs.

Results

We demonstrate that reduction of hepatic LDH achieves more effective and durable oxalate reduction than suppression of GO in mouse and non-human primate models of PHs. Continued repression of hepatic LDH in mice and non-human primates showed no adverse effects.

Conclusion

The results presented here support the further development of hepatic-specific inhibition of LDH as a highly efficient therapeutic approach to treat all types of primary hyperoxaluria.