Gene therapy could help restore vision lost to degenerative disease

Good news!

"... The team found a way to activate 'dormant' cells in the retina to reprogram them into what are called induced neuron cells, which could then be converted into new light-sensing cells to restore lost vision. ...
In doing so, the team identified a pair of transcription factors called Ikzf1 and Ikzf4, which can be expressed in Müller cells to convert them into retinal neurons. These could in turn be coaxed to replace key light-sensing cells. Other studies have found promising results doing similar things with other transcription factors. ..."

"... Although various approaches such as gene therapy exist that offer hope of slowing or blocking the progression of photoreceptor cell loss, these techniques cannot restore lost cells and are therefore not useful for patients at the advanced stages of the disease. ...
In an approach that circumvents the need for transplantation, ... team found a way to reactivate dormant cells in the retina and transform them into neural-like cells that could ultimately be used to replace cells lost in retinal degeneration. ..."

From the significance and abstract:

"Significance

The sequential production of cell types during neural development is controlled by temporal identity transcription factors, and heterochronic expression of these factors in progenitors reprograms developmental potential and promotes the production of temporally inappropriate cell types. It remains unknown, however, whether temporal factors can reprogram terminally differentiated cells. Here, we report that the combined expression of early temporal identity factors Ikzf1 and Ikzf4, homologs of Drosophila hunchback (hb), can convert uninjured retinal glia into neuron-like cells. Furthermore, we show that Ikzf1/Ikzf4 can reprogram fibroblasts into induced neurons (iNs) by altering chromatin accessibility and enabling a neuronal gene expression program. This work uncovers the reprogramming ability of temporal identity factors, opening the door to cell therapy approaches for neurodegenerative diseases.

Abstract

Temporal identity factors are sufficient to reprogram developmental competence of neural progenitors and shift cell fate output, but whether they can also reprogram the identity of terminally differentiated cells is unknown. To address this question, we designed a conditional gene expression system that allows rapid screening of potential reprogramming factors in mouse retinal glial cells combined with genetic lineage tracing. Using this assay, we found that coexpression of the early temporal identity transcription factors Ikzf1 and Ikzf4 is sufficient to directly convert Müller glial (MG) cells into cells that translocate to the outer nuclear layer (ONL), where photoreceptor cells normally reside. We name these “induced ONL (iONL)” cells. Using genetic lineage tracing, histological, immunohistochemical, and single-cell transcriptome and multiome analyses, we show that expression of Ikzf1/4 in MG in vivo, without retinal injury, mostly generates iONL cells that share molecular characteristics with bipolar cells, although a fraction of them stain for Rxrg, a cone photoreceptor marker. Furthermore, we show that coexpression of Ikzf1 and Ikzf4 can reprogram mouse embryonic fibroblasts to induced neurons in culture by rapidly remodeling chromatin and activating a neuronal gene expression program. This work uncovers general neuronal reprogramming properties for temporal identity factors in terminally differentiated cells."

Gene therapy could help restore vision lost to degenerative disease Scientists in Canada have developed a new technique that may one day help restore some sight to patients with inherited vision impairment. The regenerative therapy works by expressing genes that convert dormant cells into new light-sensing cells in the retina to replace those lost to disease.

New hope for vision regeneration Researchers led by UdeM's Michel Cayouette have found a way to reactivate dormant cells in the retina and transform them to ultimately replace cells lost in retinal degeneration.

Direct neuronal reprogramming by temporal identity factors (open access)

Fig. 1 Ikzf1/4 expression induces morphological reprogramming of MG ex vivo