Phase II Amount
$1,001,356
Major diseases, such as heart failure, Parkinson's Disease (PD), type 1 diabetes, and age-related macular de-generation, are examples of organ and systemic failure driven by damage to specific cell types. One possibletherapeutic solution is to replace the damaged cells with ex vivo engineered, physiologically functional cells toalleviate clinical symptoms. However, expensive, time-intensive, and inefficient cell reprogramming methods forgenerating transplantable therapeutic cells for degenerative disorders hinders development and clinical transla-tion of potentially transformative therapies. Our goal is to develop a highly efficient process for producing cellreplacement therapies that can be reliably manufactured at-scale to treat currently intractable diseases such asParkinson's Disease. This goal will build upon our patented and proven Cell Squeeze® technology that candeliver materials including mRNA, proteins, and peptides into sensitive primary cells. For this Phase II SBIRproposal, our overall objective is to demonstrate that with Cell Squeeze® technology we can introduce transcrip-tion factors that can increase the efficiency of transdifferentiating peripheral blood cells (PBMCs) into clinicallyrelevant dopaminergic neurons. Our central hypothesis is that we can precisely control the timing, dose, andcombinations of transcription factors to create high quality, functional cell products in greater quantities in ashorter time than is possible with current methods and free of risks associated with viral gene delivery. Support-ing this goal, we have already demonstrated that the squeeze treatment alone does not significantly affect geneexpression, we can efficiently generate neurons from iPSCs, and we can introduce multiple transcription factorsinto PBMCs to upregulate expression of key neuronal signaling pathways. The rationale is that our non-viralmethod of delivering transcription factors to drive cell fate could significantly improve the efficiency and efficacyof cells produced with fewer safety and regulatory concerns as compared to other methods of transdifferentiation.Furthermore, in comparison to allogeneic iPSC derived products, autologous cells would not require chronicimmunosuppression - a key factor to ensure long term health of the patient. In Aim 1, we seek to optimizemethods for the Cell Squeeze® technology to deliver mRNA-based transcription factors to PBMCs to drive effi-cient transdifferentiation into dopaminergic neurons (DNs). Resultant DNs will be thoroughly characterized invitro and compared to DN generated from iPSC using existing methods. In Aim 2, these DNs will be functionallyassessed in an in vivo murine PD model to support the further development into a potentially transformative celltherapy. Successful completion of these aims may support partnering opportunities with other biopharmaceuticalcompanies who are seeking differentiated cell therapy approaches in neurodegeneration.
Public Health Relevance Statement: Project narrative: Cell therapies that replace lost or damaged cells in diseases such as Parkinson's disease, type 1 diabetes, macular degeneration, and others, have shown the potential to improve patient outcome. However, current meth- ods for generating these cell therapies are difficult to translate into the clinic because of limited production effi- ciency and safety concerns related to the production methods. This research would support the development of Cell Squeeze® technology, a non-viral delivery system, for efficient cell reprogramming to potentially improve the quality of cell replacement therapies.
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