A pharmacological therapy for HNF1B-deficiency – DrugHNF1B

HNF1B is a transcription factor whose mutations represent the most common genetic cause for “Congenital Abnormalities of the Kidney and the Urogenital Tract” (CAKUT). In addition, mutations in HNF1B may also be found in adults with Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD), a rare pathological “Chronic Kidney Disease” (CKD) entity, characterized by tubular atrophy, interstitial fibrosis and progression to renal failure. HNF1B is expressed in few epithelial cell types including renal tubular cells. The pathogenic mechanisms of HNF1B-deficiency remain poorly understood. Nonetheless, they are potentially of paradigmatic importance, since the vast majority of renal traits in adult HNF1B-deficiency represent the typical hallmarks of most types of CKD. In the last years, we have contributed to show that this transcription factor plays an essential role in kidney morphogenesis and in the maintenance of renal tubular structure and functions.

For HNF1B-deficiency there is no therapeutic strategy except dialysis or transplantation. HNF1B patients carry null mutations (up to 50 % of which occur de novo) at a heterozygous state. In this context, the residual wild-type allele carried by heterozygous patients is likely to provide an insufficient level of biological activity of HNF1beta (haploinsufficiency). It is believed that HNF1B is a weak but constitutively active transcription factor and little is known about the possibility to modulate the potency of this transcription factor.

To identify small molecule compounds that may potentiate the transcriptional activity of HNF1B, we developed a biosensor that could sense and measure the transcriptional activity of HNF1B (HNF1B dependent reporter promoter) in renal tubular epithelial cell lines.

Our recent results, based on a high throughput screening on 1520 drugs (Prestwick Library), disclosed the existence of a powerful set of already FDA/EMA approved medications that could potentially be repositioned to increase the intrinsic activity of HNF1B.

Intriguingly, amongst the most active 15 drugs, ten compounds belonged to a single specific pharmacological class. In our screening, all HNF1B inducing drugs we identified did not elicit any significant increase of the biosensor readout in the absence of HNF1B (isogenic tester cell line lacking HNF1B expression), indicating that these drugs acted specifically via HNF1B.

Since heterozygous HNF1B patients suffer from haploinsufficiency, it is reasonable to assume that a pharmacological treatment that could increase the biological activity of their residual HNF1B normal allele might play a beneficial role in the attenuation of the renal dysfunction.

The major aim of this project is to validate the possible beneficial effect of these drugs on the residual activity of HNF1B in haploinsufficient models of HNF1B-deficiency in renal tubular cells from HNF1B patients (in vitro) and in a preclinical murine model of HNF1B haploinsufficiency (in vivo) during development and in postnatal life. Finally, we aim at identifying the molecular mechanism of action of these drugs on HNF1B activity.

Our research project should provide a novel (repositioned) therapeutic strategy for the treatment of a severe genetic disease affecting renal function. Importantly, if our preclinical studies will demonstrate that the selected drugs are beneficial, clinical trials could be swiftly launched in HNF1B, since these compounds are already FDA and EMA approved.