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Palmitic acid conjugation enhances potency of tricyclo-DNA splice switching oligonucleotides
Authors:Karima Relizani,Lucí  a Echevarrí  a,Faouzi Zarrouki,Cé  cile Gastaldi,Chloe Dambrune,Philippine Aupy,Adrian Haeberli,Marek Komisarski,Thomas Tensorer,Thibaut Larcher,Fedor Svinartchouk,Cyrille Vaillend,Luis Garcia,Auré  lie Goyenvalle
Affiliation:Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France;SQY Therapeutics, UVSQ, 78180 Montigny le Bretonneux, France;Université Paris-Saclay, CNRS, Institut des Neurosciences Paris Saclay, 91190, Gif-sur-Yvette, France;LIA BAHN, centre scientifique de Monaco, 98000, Monaco;SYNTHENA AG, Bern, Switzerland;INRAE Oniris, UMR 703 PAnTher, Nantes, France
Abstract:Tricyclo-DNA (tcDNA) is a conformationally constrained oligonucleotide analog that has demonstrated great therapeutic potential as antisense oligonucleotide (ASO) for several diseases. Like most ASOs in clinical development, tcDNA were modified with phosphorothioate (PS) backbone for therapeutic purposes in order to improve their biodistribution by enhancing association with plasma and cell protein. Despite the advantageous protein binding properties, systemic delivery of PS-ASO remains limited and PS modifications can result in dose limiting toxicities in the clinic. Improving extra-hepatic delivery of ASO is highly desirable for the treatment of a variety of diseases including neuromuscular disorders such as Duchenne muscular dystrophy. We hypothesized that conjugation of palmitic acid to tcDNA could facilitate the delivery of the ASO from the bloodstream to the interstitium of the muscle tissues. We demonstrate here that palmitic acid conjugation enhances the potency of tcDNA-ASO in skeletal and cardiac muscles, leading to functional improvement in dystrophic mice with significantly reduced dose of administered ASO. Interestingly, palmitic acid-conjugated tcDNA with a full phosphodiester backbone proved effective with a particularly encouraging safety profile, offering new perspectives for the clinical development of PS-free tcDNA-ASO for neuromuscular diseases.
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