Cystic Fibrosis (CF) is a fatal lung disease that affects 1 in 3500 children. F508del CFTR, the most common mutation present in 90% of CF patients, has proven difficult to treat. The two FDA approved drugs, Orkambi (lumacaftor and ivacaftor) and Symdeko (tezacaftor and ivacaftor), only improve lung function by 2-4%. Improving F508del CFTR remains a critical unmet need in CF therapeutics. One barrier to F508del CFTR correction is increased expression of the genetic modifier TGF-? in CF lung and airway epithelia. TGF-? suppresses CFTR function and nullifies the benefit of Orkambi and Symdeko. Our laboratory has discovered that the microRNA miR-145 mediates TGF-? inhibition of CFTR correction. TGF-? increases miR-145 which directly binds to the 3'-untranslated region (3'-UTR) to degrade CFTR transcripts and diminish protein expression. Loss of CFTR substrate eliminates therapeutic response. miR-145 antagonism overcomes this barrier to improve Orkambi benefit. The project pursues a novel approach to augment F508del therapeutics. We will utilize an antisense oligonucleotide (ASO) to block miR-145 binding to CFTR. We hypothesize that ASO- directed miR-145 target site blockade improves F508del CFTR correction.
Specific Aim #1 : To selectively augment F508del CFTR correction through antisense oligonucleotide blockade of the miR-145 binding site.
Specific Aim #2 : To test in vivo delivery, safety, and efficacy of antisense oligonucleotide miRNA target specific blockade in humanized CFTR mice.
These Aims will provide the necessary ?next steps? in oligotherapeutic development.
Aim 1 provides the in vitro mechanism, dosing, and efficacy data to establish the rationale for oligonucleotide targeting of the miRNA binding site to improve F508del CFTR correction.
Aim 2 utilizes the recently developed full-length humanized CFTR mouse to establish delivery feasibility, safety profile, and therapeutic response in vivo.
F508del CFTR is the most common mutation in cystic fibrosis (CF), a fatal lung pediatric lung disease. Current FDA approved correctors are only marginally effective (2-4% change in lung function), necessitating innovative strategic advances. This study will investigate the benefit, safety, and delivery of oligotherapeutics to block a microRNA binding site and improve F508del CFTR correction.
