Cellular therapies hold great promise for combating previously intractable diseases (e.g., cancer, organ failure, neuropathy, etc.). While autologous (patient-derived) cells generally are optimal, this route remains limited for many applications, cost-prohibitive, and burdensome. Allogeneic (donor-derived) pluripotent stem cells (PSCs), which can be differentiated to any cell type, provide greater scalability and cost savings. However, allogeneic cells are limited by the need to match HLA Class-1 alleles, the most genetically polymorphic region in humans. Mismatches in HLA Class 1 haplotypes lead to the self vs non-self immune response that can result in rejection of transplanted therapeutic cells. In this Phase I SBIR proposal, we will address this unmet need by developing a technology to program any HLA haplotype into a PSC on-demand. Our immune-matching technology will provide isogenic PSCs compatible with any individual, especially those with rare HLA haplotypes under-served by PSC banks. Such engineered cells can be centrally manufactured into any differentiated cell type (eg, neurons, muscle, etc). Before differentiation, the PSC can also be modified with additional genetic safeguards and efficacy enhancing features beyond just HLA Class 1 genes, thus reducing time and effort. We will establish proof-of-concept of this technology during this Phase 1 SBIR with the following goals: (1) Using gene editing, we will generate a blank human PSC line devoid of HLA-1 proteins, capable of accepting a new HLA-1 haplotype; (2) We will reconfigure and synthesize HLA Class 1 as a single linked 115-kb locus, with modular assembly features for inputting any patient haplotype on-demand; (3) We will demonstrate integration of our 115-kb donor HLA Class 1 locus into our blank stem cell line, while preserving the native regulatory information and expression levels of the HLA Class 1 genes. Once developed, our technology will provide personalized stem cells for both immunotherapy and regenerative medicine applications, leading to more efficacious and safer cell-based treatments. We anticipate licensing our technology to other companies as a cost-effective resource for allogeneic cell therapies.
NeochromosomeInc,Confidential PROJECTNARRATIVE Wewilldeveloptechnologytomakeoff-the-shelfstemcellscompatiblewiththeimmunesystemofanypatient, especiallyunderservedpatientswithrareimmunedeterminants,asasourcetomakeanyadultcell-typesuitable fornumerousapplicationsinimmunotherapyandregenerativemedicine.