Catalyst Awardee

Project Description

Enabling the effective and safe epigenetic rejuvenation with re-engineered transcription factors

Ralf Jauch, PhD | School of Biomedical Sciences, The University of Hong Kong; Jason Wong, D.Phil; Michael Huen, PhD
Competition Sponsor: Research Grants Council of the Hong Kong Special Administrative Region, China
Award Year: 2023

The Yamanaka factors Oct4, Sox2, Klf4 and c-Myc can convert somatic tissues into induced pluripotent stem cells resembling the inner cell mass of pre-implantation embryos. Induction of pluripotency is accompanied by a remarkable rejuvenation of cells from aged donors so that they epigenetically, structurally and metabolically resemble newborn tissue. The time restricted expression of all or some of these factors can repair damaged tissues in mice. However, the prolonged expression of Yamanaka factor induces tumors preventing the application of this strategy for human gene therapy. We have identified several re-engineered transcription factors (eTFs) that enhance pluripotency and direct lineage reprogramming. We hypothesize that replacing the Yamanaka factors with eTFs can decouple epigenetic rejuvenation from pluripotency induction, speeds up age reversal, enhances safety and relieves cargo restrictions for gene delivery. We have previously identified re-engineered SOX17 (eSOX17), a miniaturized SOX (miniSOX) as well as enhanced POU and KLF factors (ePOU and eKLF) with established activity to convert mouse and human cells into pluripotent or multipotent stem cells. We will overexpress combinations of these eTFs in aged human fibroblasts and measure the epigenetic and cellular rejuvenation. We aim to identify factor combinations that lose the full potential to induce pluripotency but retain the ability to rejuvenate cells akin the full complement of Yamanaka factors. Our unique eTF centered approach could lead to the identification of a strategy that not only makes rejuvenation more efficacious and delivery easier but also eliminates the imminent risk of oncogenesis associated with classical Yamanaka factors.

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