Development of a bioconjugations for carrying the MT29 molecule for the treatment of cancer-induced cachexia

Abstract

Conserving the quality of muscle tissue is a key factor for a healthier and longer life. Muscle atrophy is an adaptive process that reduces muscle mass and function in several cases, such as cachexia in cancer and sarcopenia in aging, directly affecting the quality of life and increasing mortality. In recent work, we demonstrated that the overexpression of miR-29c microRNA is capable of increasing skeletal muscle mass and function in mice and reducing genes related to muscle atrophy in vitro and in vivo. Furthermore, in our PIPE phase 1 project, we demonstrated that miR-29c was also able to inhibit muscle atrophy in cachectic mice. To advance our program, focusing on future clinical studies, in our PIPE phase 2 project (linked project), we built a new oligonucleotide-based on this microRNA, called MT29. MT29 is under development in the PIPE 2 project, where its chemical structure has been modified, and its therapeutic dose analyzed in muscle atrophy models, however, to improve its efficiency, we need its delivery (drug delivery) to be specific to the skeletal muscle, with a reduction of off-target effects and lower dose. Thus, in this PIPE invest proposal, our main objective is to improve our MT29 technology, through the construction of an efficient and specific carrying system for skeletal muscle and the treatment of cancer-induced cachexia, in line with the objectives and results of PIPE phase 2. In the first phase of PIPE invest, we developed specific bioconjugations for the muscle, and we will test two types of compositions in vitro, analyzing their efficiency and cell uptake. In the second phase, we will optimize the use in vivo, optimizing the dose, response, and therapeutic effect in mice with cancer-induced cachexia. At the end of this PIPE invest project, we will be ready for the development of IND (investigational new drug) pre-clinical studies, and with that, we will have a very important advance in the development of a disruptive product with global potential in the area of precision medicine. (AU)