Paladino, Martina (2025) Direct neuronal reprogramming: new emerging delivery technologies. [Tesi di dottorato]

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Abstract

Regenerative medicine offers promising possibilities for developing innovative therapies for various debilitating injuries and diseases, including neurodegenerative disorders. A critical aspect of cell replacement therapy in this field is the ability to generate a consistent and abundant supply of functional cell types. In the case of neurodegenerative diseases like Parkinson’s disease (PD), direct neuronal reprogramming shows great promise by allowing the generation of specific neuron types, such as the dopaminergic neurons (DANs) that are lost in PD. Previous research demonstrated that the overexpression of three transcription factors (TFs): ASCL1, NR4A2 (also known as NURR1), and LMX1A (ANL) efficiently convert both embryonic and adult somatic cells into DANs (Caiazzo et al., 2011). While other TFs have also been explored to enhance the efficiency of generating DANs, it has been confirmed that the combination of ANL is among the most effective. The overexpression of these TFs has been achieved through viral transduction, which was successful for the direct reprogramming of DANs. However, this approach carries risks, such as insertional mutagenesis and genomic variability, which can limit its clinical applicability. Additionally, even though induced DANs (iDANs) exhibit characteristics similar to primary DANs, they may still face rejection by the immune system after transplantation. An alternative approach is in vivo direct reprogramming of iDANs, which could circumvent the immune rejection issues associated with transplantation and provide a more robust and clinically viable strategy for treating neurodegeneration by replacing lost neurons. Given the risks correlated to viral delivery methods, using lipid nanoparticles (LNPs) for mRNA delivery represents a promising non-viral option. LNPs are recognized as advanced vectors for efficiently delivering nucleic acids and are already used in some clinical applications. We demonstrated that LNPs can successfully overexpress ANL factors leading to the generation of DANs, both in vitro and in vivo, underscoring the potential of this approach for future reprogramming applications.

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