CELL PENETRATING PEPTIDE-CONJUGATED MORPHOLINO: A NOVEL COMPOUND TO RESCUE SMA IN A SYMPTOMATIC PHASE

Cell Penetrating peptide-conjugated Morpholino: a novel compound to rescue SMA in a symptomatic phase Spinal muscular atrophy (SMA) is a motor neuron disease and the leading genetic cause of infant mortality. Recently approved SMA therapies have transformed a deadly disease into a survivable one, but these compounds show an effective rescue only if administered in the early stages of the disease. Basing on these evidence is clear that safe, symptomatic-suitable, non-invasive treatments with high clinical impact across different phenotypes are urgently needed. To address these issues, we conjugated antisense oligonucleotides with Morpholino (MO) chemistry, that has shown to increase SMN protein levels, to cell-penetrating peptides (CPPs) for better cellular distribution. Systemically administered MOs linked to r6 and (RXRRBR)2XB peptides crossed the blood-brain barrier and increased SMN protein levels remarkably, causing striking improvement of survival, neuromuscular function, and neuropathology, even in symptomatic SMA animals. This thesis demonstrates that MO-CPP conjugates can significantly expand the therapeutic window through minimally invasive systemic administration, opening the path for clinical applications of this strategy.