Kidney Week 2025 Annual Meeting-Monogenic Kidney Disease: Mechanistic Insights and Therapeutic Approaches

Video Transcription

Video Summary

This recorded conference session on “Monogenic Kidney Diseases: Mechanistic Insights and Therapeutic Approaches” featured multiple talks highlighting new disease mechanisms and emerging therapies.<br /><br />Damaris Neshama presented work in tuberous sclerosis complex (TSC) kidney disease showing that mTOR hyperactivation increases phospho–Ser/Thr-Pro targets and activates the prolyl isomerase PIN1 via reduced inhibitory phosphorylation. Pharmacologic PIN1 inhibition (sulfopin) reduced cyst burden in TSC1 knockout mice without directly suppressing mTOR, and appeared to act through splicing-factor targets (SRRM2, SRSF2/SC35). RNA-seq revealed widespread alternative splicing changes in TSC kidneys that were reversed by sulfopin, including a PKD1 splicing event.<br /><br />Olivier Devuyst described allele-selective antisense oligonucleotides (ASOs) for ADTKD-UMOD to selectively reduce mutant uromodulin while sparing protective wild-type UMOD. A lead gapmer reduced mutant mRNA and protein aggregates in vivo, lowered ER stress, improved urate handling, and reduced inflammation, with strong kidney/TAL delivery.<br /><br />Yili Fang discussed a UMOD deletion model implicating mesencephalic astrocyte-derived neurotrophic factor (MANF) as protective: MANF deficiency increased ER calcium leak, mitochondrial calcium overload, impaired mitochondrial biogenesis/respiration, and enhanced inflammatory signaling.<br /><br />Sante Princiero Berlinguerio showed cystinosis proximal tubule cells (isolated from patient urine) have slowed glycolysis/TCA metabolism and reduced NAD. Combining cysteamine with an NAD precursor improved glycolysis and ATP production in vitro and improved metabolic profiles in zebrafish.<br /><br />Shohei Kuraoka presented organoid-on-chip ARPKD models recapitulating distal nephron dilation, identifying SPTAN1 loss as a driver of RAC1 activation, altered calcium signaling, and cystogenesis; connecting tubules may be a key cyst origin.<br /><br />Chunxi Song demonstrated that editing just six nucleotides in the PKD1 3’UTR miR-17 seed site restores PKD1 expression and slows cystic disease in mice; steric-blocking oligos also increased PC1 and reduced cyst growth in mouse/human cells.<br /><br />Xiaofang Wang reported a pregnancy-associated plasma protein A (PAPP-A) neutralizing monoclonal antibody reduced disease severity in PKD1RC/RC mice, comparable to tolvaptan, with possible combination potential.<br /><br />Shu Hai Liang (Anatra) presented “Agile” ASOs that directly enhance PKD1 translation, increasing PC1 in cells and mouse kidney with durable effects and functional improvement in cyst assays.

Asset Subtitle

Moderator(s): Andreia Watanabe, Terry Watnick

Presentation(s):

Alternative Splicing Dysregulation by Pin1 Mediates Tuberous Sclerosis Kidney Disease - Morris Nechama
Allele-Selective Antisense Oligonucleotide Targeting Uromodulin Reduces Toxic Aggregates and Rescues Kidney Damage in Models of UMOD-Related Autosomal Dominant Tubulointerstitial Kidney Disease - Olivier Devuyst
Mesencephalic Astrocyte-Derived Neurotrophic Factor Orchestrates Endoplasmic Reticulum (ER)-Mitochondrial Calcium Homeostasis in Genetic CKD - Yili Fang
Targeting Metabolic Dysfunction in Cystinosis Proximal Tubular Epithelial Cells - Sante Princiero Berlingerio
Deciphering the Effect of RAC1-SPTAN1 in Autosomal Recessive PKD (ARPKD) Cystogenesis Using Multifaceted Models - Shohei Kuraoka
Endoplasmic Reticulum-Mitochondrion Disconnection Promotes Epigenetic Rewiring and Cystogenesis in PKD - Biswajit Padhy
Precise Editing of the Central Six Nucleotides in the Pkd1-3’UTR miR-17 Binding Motif Is Sufficient to Restore Pkd1 and Slow PKD Progression - Chunzi Song
Protective Effect of a Human Pregnancy-Associated Plasma Protein A IgG Monoclonal Antibody in an Orthologous ADPKD Mouse Model - Xiaofang Wang
Antisense Oligonucleotide-Mediated Polycystin 1 Upregulation by Enhancing PKD1 Translation Has the Potential to Treat ADPKD - Xuehai Liang

Note: Continuing education credits are not being offered for this session.

Meta Tag

Date 11/7/2025

Pathway 1 Genetic Diseases and Development

Session ID 519858

Keywords

Monogenic kidney diseases

Tuberous sclerosis complex kidney disease

mTOR hyperactivation

PIN1 inhibition sulfopin

Alternative splicing SRRM2 SRSF2

ADTKD-UMOD allele-selective antisense oligonucleotides

Mutant uromodulin ER stress

MANF protective factor

Cystinosis proximal tubule metabolism

NAD precursor with cysteamine therapy

ARPKD organoid-on-chip SPTAN1 RAC1

PKD1 3'UTR miR-17 seed site editing

PAPP-A neutralizing antibody in polycystic kidney disease