Cell-penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model

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 a wide spectrum of clinical response and effective rescue only in the early stages of the disease. Therefore, safe, symptomatic-suitable, non-invasive treatments with high clinical impact across different phenotypes are urgently needed. We conjugated antisense oligonucleotides with Morpholino (MO) chemistry, which 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 gates can significantly expand the therapeutic window through minimally invasive systemic administration, opening the path for clinical applications of this strategy.

Automated summary

Spinal muscular atrophy is a motor neuron disease and the leading genetic cause of infant mortality. Recently approved therapies have transformed this deadly disease into a survivable one, but their clinical response is wide-ranging and effective only in the early stages. Therefore, there is an urgent need for safe, symptomatic-suitable, non-invasive treatments.