Juvena Therapeutics developed JUV-161 as a recombinant fusion protein to agonistically target MAPK/ERK and PI3K/AKT cascades. These pathways are the major signaling mediators in skeletal muscle to enhance myogenesis, muscle survival, metabolism, and strength.
To advance the preclinical development of JUV-161 for myotonic dystrophy type 1 (DM1), Juvena Therapeutics developed a pan-inducible, TREDT960I transgenic mouse model containing a human genomic segment containing exons 11-15 of DMPK gene with 960 interrupted CTG repeats (CUG960) under direction of the tetO (tet-responsive element) promoter. This CUG960/+ murine model encompasses the key aspects of DM1 muscle deterioration, as shown using both functional and histological testing to confirm distal muscle wasting and RNA foci accumulation in impacted tissue. Administration of JUV-161 in this DM1 mouse model resulted in significant improvements in grip strength, coinciding with significantly increased tibialis anterior cross-sectional area and an increased density of fast-twitch type-2X/B muscle fibers in the soleus in both male and female mice. Binding assays and receptor sequence homology across species (BLASTP), reflected potential clinical translatability of the preclinical results obtained in a DM1 mouse model. Additionally, receptor binding along with evaluation of receptor sequence homology (>94% across all species evaluated) allowed selection of the pharmacologically relevant species (rat and dog) for the PK/PD and nonclinical safety studies. Based on the results from these studies and the promising activity of JUV-161 in preclinical and nonclinical studies, Juvena Therapeutics is planning to evaluate the potential therapeutic benefit of JUV-161 in adult-onset DM1 patients in 2024. JUV-161 treatment could improve muscle strength, endurance, mass, and glucose regulation, leading to reduced atrophy together with faster walk speeds and reduced fall rates, in adult-onset DM1 patients.
Funding: California Institute of Regenerative Medicine (CIRM TRAN1-12890); National Institute of Aging (NIA R43AG071181). Acknowledgments: The TREDT960I transgenic mouse model was licensed from the Baylor College of Medicine, and crossed with R26-M2rtTA(+/+) mice containing the reverse tetracycline transactivator knock-in. The authors acknowledge scientific advice on DM1 model breeding and validation from Dr. Thomas Cooper, Baylor College of Medicine.