Nomlabofusp, a Fusion Protein of Human Frataxin and a Cell Penetrant Peptide, Delivers Mature and Functional Frataxin into Mitochondria

• Published in: The AAPS journal Vol. 27; no. 3; p. 68
• Main Authors: Baile, Matthew G., Jones, John, Sahr, Natasha, Shankar, Gopi
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 26.03.2025; Springer
• Subjects: Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cell Line; Cell-Penetrating Peptides - administration & dosage; Ethylenediaminetetraacetic acid; Frataxin; Friedreich Ataxia - drug therapy; Friedreich Ataxia - metabolism; Gene expression; Genes; HEK293 Cells; Humans; Iron-Binding Proteins - administration & dosage; Iron-Binding Proteins - genetics; Iron-Binding Proteins - metabolism; Iron-Binding Proteins - pharmacokinetics; Lubrication and lubricants; Medical research; Medicine, Experimental; Mice; Mitochondria - metabolism; Peptides; Pharmacology/Toxicology; Pharmacy; Rats; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacokinetics; Research Article; Cell penetrant; Friedreich’s ataxia; Mitochondria; Frataxin; Nomlabofusp
• ISSN: 1550-7416; 1550-7416
• DOI: 10.1208/s12248-025-01054-5

Friedreich’s ataxia is a rare, progressive, genetic disorder, the root cause of which is a significant deficiency in the mitochondrial protein frataxin. Frataxin is ubiquitously expressed, but its deficiency results in a variety of debilitating symptoms, with disease severity, rate of progression and age of onset inversely correlating with tissue frataxin levels. Nomlabofusp is a novel cell penetrant peptide based recombinant fusion protein designed to enter cells and deliver human FXN into the mitochondria. Using immunofluorescence staining and western blot we show that frataxin delivered by nomlabofusp is detected in the mitochondria of H9c2 and SH-SY5Y cells. Also in these cells, and in C2C12 and HEK293 cells, we demonstrate the presence of mature frataxin after nomlabofusp exposure. Finally, using buccal swab tissue samples taken from study subjects in a Phase 1 clinical trial who received nomlabofusp, we show increases in mature frataxin levels along with marked changes in gene expression post-administration suggesting intracellular pharmacodynamic activity. Together, these results demonstrate that nomlabofusp enters the cell and localizes to the mitochondria, releasing mature frataxin that appears to be biologically active and support the use of nomlabofusp as a potential treatment for patients with Friedreich’s ataxia. Graphical Abstract