The endosomal escape vehicle platform enhances delivery of oligonucleotides in preclinical models of neuromuscular disorders.

Autor:	Li X; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Kheirabadi M; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Dougherty PG; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Kamer KJ; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Shen X; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Estrella NL; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Peddigari S; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Pathak A; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Blake SL; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Sizensky E; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Genio CD; Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA., Gaur AB; Dartmouth Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA., Dhanabal M; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Girgenrath M; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Sethuraman N; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA., Qian Z; Entrada Therapeutics, One Design Center Place, Suite 17-500, Boston, MA 02210, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Jun 29; Vol. 33, pp. 273-285. Date of Electronic Publication: 2023 Jun 29 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.06.022
Abstrakt:	Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of this endosomal escape vehicle platform in preclinical models of muscular dystrophy with distinct disease etiology. An endosomal escape vehicle-conjugated, splice-modulating oligonucleotide restored dystrophin protein expression in striated muscles in the mdx mouse, a model for Duchenne muscular dystrophy. Furthermore, another endosomal escape vehicle-conjugated, sterically blocking oligonucleotide led to knockdown of aberrant transcript expression levels in facioscapulohumeral muscular dystrophy patient-derived skeletal muscle cells. These findings suggest a significant therapeutic potential of our endosomal escape vehicle conjugated oligonucleotides for targeted upregulation and downregulation of gene expression in neuromuscular diseases, with possible broader application of this platform for delivery of intracellular biological agents. Competing Interests: X.L., M.K., P.G.D., K.J.K., X.S., N.L.E., S.P., A.P., S.L.B., E.S., M.D., M.G., N.S., and Z.Q. are employees of and hold stock in Entrada Therapeutics. (© 2023 The Author(s).)
Databáze:	MEDLINE
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