Targeting the maladaptive ER-stress mediator Chop using LNAplus™ antisense-oligonucleotides in diabetic nephropathy

Diabetic nephropathy (dNP) is the most common cause of end-stage renal disease worldwide. Established therapies like angiotensin-converting-enzyme inhibitors (ACEi) delay but fail to prevent dNP progression. Efficient therapies are lacking and dNP continues to be an unmet medical need. Recently a maladaptive ER-stress response has been identified as an important factor in the pathogenesis of dNP. A key molecule conferring the renal maladaptive ER-stress response is C/EBP homologous protein (Chop). We hypothesized that Chop is a promising molecular target for novel dNP therapies. As Chop is an intracellular transcription factor it falls into the category “difficult to target” and represents an optimal target for antisense-oligonucleotides (ASOs).

We designed locked nucleic acid (LNA)plus™ ASOs specific for mouse or human Chop using our Oligofyer™ bioinformatics system. For in vivo proof-of-concept experiments eight-week-old db/db mice were treated for eight weeks with 1 mg/kg of control or mouse Chop-specific LNAplus™ ASO. We analyzed urinary output, urine albumin-to-creatinine ratio (UACR), histopathological damage and expression of ER-stress response factors at the end of the in vivo intervention.

Treatment of mice with the Chop-specific LNAplus™ ASO (but not with the control oligonucleotide) resulted in a Chop knockdown in kidneys of > 80%. Chop ASO therapy significantly decreased the UACR, urinary output and histopathological damage.

In conclusion, targeting the maladaptive ER-stress mediator Chop with LNAplus™ ASOs is a promising novel approach for the treatment of dNP. Further ex vivo and in vitro analyses and studies that investigate the combination with current state of the art therapies are ongoing.