Kidney Week

Abstract: TH-PO435

RGLS8429-Mediated miR-17 Inhibition Leads to Acute PKD1/2 De-repression and Ameliorates Preclinical ADPKD

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Lakhia, Ronak, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Ronak Lakhia, MD

• Alvarez, Jesus A., The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Jesus A. Alvarez

• Ramalingam, Harini, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Harini Ramalingam, PhD

• Cobo-Stark, Patricia, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Patricia Cobo-Stark

• Biggers, Laurence Michael, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Laurence Michael Biggers

• Huang, Jianfeng, Regulus Therapeutics Inc, San Diego, California, United States

Jianfeng Huang, PhD

• Valencia, Tania M., Regulus Therapeutics Inc, San Diego, California, United States

Tania M. Valencia, PhD

• Lee, Edmund Chun Yu, Regulus Therapeutics Inc, San Diego, California, United States

Edmund Chun Yu Lee, PhD

• Patel, Vishal, The University of Texas Southwestern Medical Center, Dallas, Texas, United States

Vishal Patel, MD

Background

ADPKD is caused by reduced PKD1/2 gene dosage. However, drugs that improve PKD1/2 levels are not available. We have shown that microRNA-17 directly represses PKD1/2 and aggravates ADPKD progression. Thus, our goals were to characterize the next-gen anti-miR-17 drug RGLS8429 and its impact on PKD1/2 and ADPKD.

Methods

We treated murine and human ADPKD kidney cell lines and mouse models with PBS, control oligo, or RGLS8429 to assess for miR-17 inhibition, PKD1/2 de-repression, and therapeutic efficacy before or after PKD onset and in synergy with tolvaptan. We used multi-omic analyses to uncover early cellular and molecular events modulated by RGLS8429.

Results

RGLS8429, a 9-nt oligonucleotide, inhibits the miR-17 miRNA family and de-represses direct miR-17 targets, including PKD1/2. It reduces 3D cyst size in multiple mouse and human ADPKD cell lines. In the Ksp^Cre;Pkd1^F/RC model, RGLS8429 effectively delivers to kidney cysts, even if administered after significant disease, and leads to a rapid Pkd1/2 de-repression within just 3 days of starting treatment. Remarkably, early RGLS8429 treatment prevents cyst formation, while treatment initiation at later disease stages stabilizes cyst burden and prolongs survival, with ~50% of mice surviving nearly 1 year and, in some cases, showing disease resolution. Further, we demonstrate therapeutic synergy between RGLS8429 and tolvaptan in the Pcy model. Finally, we produced a high-resolution cellular atlas by profiling >160,000 single nuclear transcriptomes (snRNA-seq), uncovering 26 kidney cellular clusters. We noted rapid transitions in cellular states within 10 days after treatment initiation, with a reduced abundance of immune cells and principal cells with fibroinflammatory signatures and the emergence of ‘healthier’ proximal tubule cell types. We used a multi-layered, sequential RNA-seq and proteomics approach to map early molecular events onto these cellular neighborhoods.

Conclusion

RGLS8429-mediated acute pharmaceutical PKD1/2 de-repression holds the potential for a significant disease-modifying effect in ADPKD. This promising drug is currently being evaluated in Phase 1b ADPKD clinical trials.

Funding

• NIDDK Support – Regulus Therapeutics