Direct reprogramming of human fibroblasts into iNPCs

This figure has been published in SciTech Europa Issue 26, pp 132-33; you can read the full article here.

Real patient samples affected by ALS/MND and other neurodegenerative disorders visit the clinic in at the Hallamshire Hospital in Sheffield everyday and this gives us the opportunity to collect skin biopsies for cell reprogramming (Step 1 & 2). The novel direct reprogramming protocol that Drs Meyer and Ferraiuolo generated (Step 3) produces induced neural progenitor cells (iNPCs) that can be then differentiated in neurons, astrocytes and oligodendrocytes. These cells recapitulate the disease mechanisms and hallmarks identified in post-mortem tissues, such as protein aggregates, thus giving us the opportunity to use disease-relevant readouts. Our team has then developed 2D and 3D culture systems to observe the cross-talk between neurons and astrocytes and identify novel mechanisms of toxicity (Step 5), which can then be targeted via small molecules or gene therapy approaches. We have developed high-throughput screening platforms in 384-well plates to be able to screen for molecules that decrease neuronal death, as well as protein aggregates (Step 6). As not all patients are the same, we have identified groups of responders and non-responders to specific drugs and therapeutic agents. With the use of transcriptomics, we aim to identify gene signatures that discriminate between responders and non-responders groups to inform patient stratification for future clinical trials and approved therapies.

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