CMT 1A results from the duplication of the myelin protein 22 gene (PMP22) in Schwann cells. This causes excessive production of the PMP22 protein which disrupts the myelination process of peripheral nerves and ultimately results in axonal loss and muscle wasting over an extended period.
One promising approach to reducing PMP22 expression are antisense oligonucleotides (ASOs) targeted to PMP22 RNA within Schwann cells. ASOs are single stranded sequences of synthetic nucleic acids that are designed to bind to a specific RNA sequence. Binding of ASOs to that RNA can modulate protein expression. However, a significant challenge is their effective delivery, as they can be easily degraded in the body, necessitating high doses that pose toxicity risks.
Nanite has been addressing delivery vehicles that can efficiently and safely transport nucleic acid payloads. While viral vectors are advanced gene delivery tools, they are limited by immunogenicity and cannot be dosed repeatedly. Polymer-based encapsulation—wrapping medicines in tiny polymer containers-which can release the drugs slowly, keep them stable and deliver them to specific cells or tissues, making treatments more effective with fewer side effects—and delivery of nucleic acids have been considered, but the vast chemical design space of polymers has hindered progress. Finding an effective polymer delivery system for CMT1A requires overcoming these challenges while maintaining the stability of the nucleic acid cargo and allowing for repeated dosing over an extended period.
Nanite aims to overcome this barrier via novel machine learning approaches, which enable rapid design and iterative improvement of large numbers of chemically diverse polymeric gene delivery vehicles. The first year of their project, they were able to generate a library of polymers with good binding profiles using machine learning, characterize the polymers, examined ASO payload activity in vitro, and verified polymer encapsulation of the ASO payload in vitro.
