Therapeutics
IN VIVO CELL
REPROGRAMMING current status and potential clinical applications
In Vivo Cell Reprogramming, or IVR, is a new technology that can be used to develop cures for incurable diseases. Using a combination of protein, small molecule or RNA drugs, one type of cell (substrate cell) can be reprogrammed to another type of cell (product cell). The product cells are usually the damaged or depleted cells associated with certain diseases and the substrate cells can be any type of cell that is abundant either in proximity to or inside the affected organs. IVR potentially combines the advantages of drug-based and cell-based therapies while avoiding the shortcomings of both.
E
mbryonic stem cells (ESCs) are capable of differentiating into every type of cell in the human body. Previously, differentiation from ESCs to progenitor cells and eventually to somatic cells was believed to be irreversible; cell fate was thought to be committed. However, this paradigm has been overturned by the emergence and accept- ance of the cell reprogramming phenomenon. The concept of cell reprogramming is not new. It emerged in the 1960s: somatic cells were repro- grammed to stem cells using somatic cell nuclear transfer (SCNT)1. The groundbreaking discovery of induced Pluripotent stem cells (iPSC) by Dr Yamanaka and colleagues in 2006 once again indi- cated that cell fate can be reversed2. More impor- tantly, Dr Yamanaka and his team showed that the change of cell fate can be accomplished using defined factors – in this case, by forced expression of four transcription factors: Oct4, Sox2, Klf4 and c-Myc. The field of cell reprogramming has exploded since then. In 2008, Dr Melton’s group demonstrated that pancreatic exocrine cells can be
Drug Discovery World Summer 2011
transdifferentiated to cells in vivo via viral trans- duction of several genes encoding pancreatic and cell transcription factors, namely, Ngn3 (Neurog3), Pdx1, and MafA3. More recently, researchers have directly reprogrammed fibroblasts into both functional neurons4 and into functional cardiomyocytes5 in vitro using the same technique. All these exciting discoveries have raised an intriguing question: can we directly reprogramme one type of cells to another type of cells in vivo (or in situ) for therapeutic purposes? In this article, we will discuss the concept of in vivo cell reprogram- ming, its potential clinical applications and possi- ble challenges.
Target: difficult diseases
Although great advances have been made in bio- medical research, scientists and clinicians are still looking for effective treatments for some of the most devastating diseases, such as diabetes, car- diovascular diseases, spinal cord injury, Parkinson’s disease and Alzheimer’s disease. Some
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By Dr Shili Wu, Jonathan Pang, Bobby Baravati, Jun Bao and Dr Yong Zhu
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