Exosome-based therapy for spinal cord injury- a holistic approach

Patients with spinal cord injury (SCI) usually suffer from permanent neurological deficits, while spontaneous recovery and therapeutic efficacy are limited. Exosomes are natural membrane vesicles (50−150 nm) of endosomal origin, secreted by various cells including mesenchymal stem cells (MSCs). They have emerged as promising nanocarriers for drug delivery and targeted therapy, as alternatives to stem cell therapy. Phosphatase and tensin homolog (PTEN) is expressed in neurons and regenerating axons and plays a vital role in controlling the regeneration of corticospinal neurons via downregulating cytoplasmic mammalian target of rapamycin (mTOR) activity. Here, we present an exosome-based therapy for the treatment of spinal cord injuries. Our product includes a complete bioprocess, starting with isolation from 3D cultured bone-marrow-derived mesenchymal stem cells with an increased yield, followed by loading of the exosomes with PTEN-siRNA (exo-PTEN) and intranasal administration in rats for in vivo studies. First, our exosomes are biophysically and biochemically characterized enabling a full control of our product and a batch-to-batch comparison. We showed that MSC-Exosome given intranasally are able to cross the Blood-brain-barrier and home to the spinal cord lesion. Second, we observed a loading of around 65% of the exosomes with the PTEN- siRNA (exo-PTEN) using only incubation. We have a number of siRNA molecules with proprietary sequences, internal modifications, and loading moiety. These sequences showed a significant decrease in RNA and protein PTEN expression. In vivo studies showed that intranasal Exo-PTEN treatment induces bladder and motor recovery. These results have significant clinical therapeutic applications for SCI and other neurological diseases with neuroinflammation.