About microRNAs.

We believe that targeting pathways of human disease with antisense oligonucleotides targeting RNA biology represents a novel and potentially powerful therapeutic approach for multiple diseases.

We are beginning this work with therapies designed to target microRNA regulation of protein expression. MicroRNAs are small, naturally occurring, non-coding RNAs that function as important regulators of gene expression of messenger RNA (mRNA) and play a role in multiple cellular processes. They do this by binding specific mRNA and blocking translation, leading to control of gene expression and direct degradation of target mRNA.

These naturally occurring non-coding RNAs were first discovered in 1993, and have been identified in almost every mammalian species, including humans. This conservation across species supports the important role of these regulatory RNA elements in mammalian biology.

MicroRNAs play an integral role in numerous biological processes, including the immune response, cell-cycle control, metabolism, viral replication, stem cell differentiation, and human development. There are about 2,600 predicted mature human microRNAs, 600 of which are considered to be well validated and provide a large space of novel target opportunities. Indeed, microRNA expression or function is significantly altered in numerous diseases including cancer and fibrosis, as well as in CNS, metabolic and inflammatory disorders.

We are currently focused on genetic kidney diseases, where we have evolved our foundational technology and demonstrated the ability to preferentially distribute our therapeutic molecules to the kidney in both preclinical models and in patients.

Mechanism of action.

Pipeline.

Pipeline

Our clinical pipeline centers on two orphan kidney diseases of high unmet need: Autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome.

Our ADPKD product candidate, RGLS8429, is being evaluated in a Phase 1 clinical trial. Our Alport syndrome product candidate, lademirsen, which is being developed in partnership with Sanofi, is being evaluated in a global Phase 2, randomized, placebo-controlled study.

See our publications >

About ADPKD.

About ADPKD

ADPKD is an orphan disease of high unmet need that effects approximately 160,000 diagnosed individuals in the U.S.

Total Patient Population

  • 12M

    Globally

  • 500K

    In the U.S.

50%

of patients develop end stage renal disease by age 60 and require dialysis or transplantation

The only existing FDA-approved agent for ADPKD, tolvaptan, carries a boxed warning for potential fatal liver injury

CAUSES

ADPKD is caused by a mutation of either the Pkd1 or Pkd2 genes, which leads to the formation and proliferation of fluid-filled cysts in the kidneys, and ultimate loss of kidney function over time.

About RGLS8429

We are advancing our next-generation, anti-miR-17 compound, RGLS8429, to treat ADPKD. Our work in this disease area builds on the positive clinical results seen with our first-generation compound. RGLS8429 is supported both by robust data in preclinical models, where we have seen clear improvements in kidney function, size, and other measures of disease severity, as well as a superior pharmacologic profile.

Notably, we have also seen additive efficacy in animal models of ADPKD when combining our first-generation ADPKD candidate with the only FDA-approved agent for the disease, tolvaptan, an important commercial consideration for those that can tolerate tolvaptan.

RGLS8429 Mechanism of Action

Pkd1 or Pkd2 gene mutations are associated with an increase in the expression of a specific microRNA (miR-17), which directly leads to the repression of its target genes and as a result, a decrease in the proteins they encode, polycystins 1 and 2 (PC1 and PC2).

RGLS8429 Mechanism of Action

We believe treating ADPKD with an anti-miR-17 therapy will correct the underlying pathology of ADPKD by inhibiting miR-17 function in the kidney.

RGLS8429 Mechanism of Action

miR-17 inhibition will enable increased translation of target mRNA.

RGLS8429 Mechanism of Action

…leading to increased PC1 and PC2 protein levels and reduction of cyst growth.

About Alport Syndrome.

Alport syndrome is a genetic kidney disease for which there are no existing FDA-approved therapies.

It is estimated that between 30,000 and 60,000 individuals in the United States live with Alport Syndrome. (NORD)

Healthy Kidney

Alport Kidney

GENETIC CAUSE

Alport syndrome is caused by mutations in the type IV collagen genes: Col4A3, Col4A4, and Col4A5. Type IV collagen plays a critical role in maintaining the integrity of the glomerular basement membrane (GBM) which lines the kidney. The genetic mutation present in Alport Syndrome leads to fibrosis and subsequent thickening of the GBM, and ultimate impairment of the filtration role of the kidney.

Individuals with Alport syndrome experience a progressive loss of kidney function, ultimately leading to end stage renal disease. The collagen mutations in the disease also impact hearing and vision due to additional fibrosis in those tissues.

Most individuals with the disease require dialysis or kidney transplantation by early adulthood, or face early death. Young males with the disease are particularly at risk due to their genetic inheritance and may progress to kidney failure in their 20s or 30s.

About Lademirsen

Our Alport syndrome product candidate, lademirsen, is being developed by Sanofi through a research collaboration to discover and develop oligonucleotides that inhibit miR-21 and the fibrosis associated with this microRNA in kidney disease.

In preclinical studies, lademirsen demonstrated potent inhibition of miR-21 in vitro and in vivo, and in an experimental model of Alport syndrome demonstrated a decrease in the rate of progression of renal fibrosis, an increase in survival of the mice by up to fifty percent, and provided an additive benefit in combination with an anti-hypertension drug which is used to manage increased blood pressure, one of the clinical consequences of the disease.

A Phase 2, randomized, placebo-controlled study of lademirsen in patients with Alport syndrome is currently underway at sites across the globe. Final data are expected in the first half of 2023.

Ladmirsen Mechanism of Action

miR-21 expression is significantly elevated in Alport syndrome.

Ladmirsen Mechanism of Action

Lademirsen is a single stranded oligonucleotide that is designed to bind to, and thereby inhibit the function of miR-21 for the treatment of Alport syndrome.

Ladmirsen Mechanism of Action

miR-21 inhibition will enable increased translation of de-repressed target mRNAs that are dysregulated in disease.

Ladmirsen Mechanism of Action

Increased protein levels should lead to decreased kidney fibrosis and inflammation, and improved renal function for the treatment of Alport syndrome.