A new treatment strategy for inherited dementia and Alzheimer’s disease was identified using stem cells derived from affected neurons. The study, entitled, “Restoration of Progranulin Expression Rescues Cortical Neuron Generation in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia” was recently published in the International Society of Stem Cell Research’s journal, Stem Cell Reports.
Frontotemporal dementia (FTD) is estimated to comprise half of dementia cases in patients younger than the age of 60. Up to 40% of FTD patients have a familial history, due to genetic mutations in the microtubule-associated protein tau gene (MAPT), progranulin gene (GRN), or C9orf72 gene. The majority of FTD-causing mutations in the GRN are predicted to result in functional null alleles, causing haploinsufficiency. Progranulin (PGRN) has been found to have neurotrophic function in vitro and in vivo. Human somatic cell reprogramming to a pluripotent state (iPSCs) can create human disease models in vitro, such as FTD, using patient-derived iPSCs.
In a recent news release, senior author Catherine Verfaillie of KU Leuven (University of Leuven) in Flanders, Belgium said, “Use of induced pluripotent stem cell (iPSC) technology”–which involves taking skin cells from patients and reprogramming them into embryonic-like stem cells capable of turning into other specific cell types relevant for studying a particular disease–“makes it possible to model dementias that affect people later in life.”
“iPSC models can now be used to better understand dementia, and in particular frontotemporal dementia, and might lead to the development of drugs that can curtail or slow down the degeneration of cortical neurons,” added Verfaillie.
Verfaillie led a team of researchers in evaluating cortical neuron development from FTD-patient-derived iPSCs, as FTD is characterized by selective neurodegeneration of the frontal and/or temporal cortex. Three patients carrying the GNR mutation were examined and were found to have impaired immature cells. They then observed in iPSCs a defective signaling pathway called Wnt, identified to play a critical role in neuronal development.
Results showed that gene correction or treatments with a compound that can inhibit the Wnt signaling pathway restored the ability of the iPSCs to turn into cortical neurons. “Our findings suggest that signaling events required for neurodevelopment may also play major roles in neurodegeneration,” senior co-author Philip Van Damme said. “Targeting such pathways, as for instance the Wnt pathway presented in this study, may result in the creation of novel therapeutic approaches for frontotemporal dementia.”