SCRMC researchers to investigate mechanisms and models related to Spina Bifida and Fragile X Syndrome

Stem Cell and Regenerative Medicine Center (SCRMC) investigators at the University of Wisconsin–Madison will be engaging in two novel, neural research projects thanks to a gift from the Wisconsin Alumni Research Foundation (WARF).

The projects will seek to create cell culture models capable of predicting the risk of Spina Bifida (SB) and explore the molecular mechanisms that contribute to neurodevelopmental disorders such as fragile X syndrome (FXS). Both projects will use induced pluripotent stem cell (iPSC) lines, which are cells derived from adult somatic cells that have been reprogrammed to become pluripotent, in other words, they can differentiate into any cell or tissue in the body. The iPSCs generated from these projects will be deposited to WiCell and shared with the scientific community.

Randolph Ashton, PhD

The research, entitled ‘An iPSC Resource for Spina Bifida (Myleomeningocele) Precision Medicine’, will be led by SCRMC associate director, WID faculty member, and CEO and co-founder of Neurosetta, LLC, Randolph Ashton who will work with the UW Human Stem Cell Core to reprogram patient skin cells collected by Bermans Iskandar, MD and Brady Lundin, MD, PhD into induced pluripotent stem cells (iPSCs). With each patient’s iPSC cell lines, the Ashton labwill create a personalized cell culture model, which the researchers hope will be capable of displaying whether or not the source patient has SB.

“If the cell culture model can be used to predict whether the patient has SB, then it will demonstrate clinical relevance of a novel SB modeling platform, which can be used to investigate the genetics underlying SB risk,” says Ashton.

Ashton also noted that while the primary goal is to develop a cell culture model to detect whether someone has a genetic predisposition for SB (i.e., SB risk), it may also be possible to use this research to screen for potential ways to reduce the risk of SB in the patient’s progeny.

“If this project is successful, then it would seed a much larger research proposal between the UW Pediatric Spina Bifida Clinic and faculty from multiple UW-Madison science and engineering departments to create the first-ever Center for Spina Bifida Precision Medicine,” says Ashton.

He also added that there are very limited funding sources for creating iPSC lines to conduct such preliminary studies, so this funding is key to moving this type of research forward.

Likewise, the project entitled, “Human iPSC lines from fragile X patients with distinct cognitive levels,” led by professor of Neuroscience and Waisman investigator, Xinyu Zhao, will use the funding to develop a basic understanding of the mechanism underlying phenotypic diversity, which will pave the way for future precision medicine and discovery.

Xinyu Zhao, PhD

“The funding allows us to derive iPSCs from patients with deep clinical phenotyping, which is important for precision medicine and better clinical trial design,” says Zhao.

During this stage of research, Zhao plans to investigate the molecular mechanisms that contribute to neurodevelopmental disorders to better understand why severity differs among patients who are affected by the same genetic mutations. While this could apply to a variety of disorders, Zhao has been studying a single gene disorder, FXS, which is the most common heritable cause of intellectual disability and a top contributor to autism spectrum disorders.

“Despite being a single-gene disorder, individuals with FXS have wide variation in clinical presentations and responses to treatment,” says Zhao. “Elizabeth Berry-Kravis, MD, is a leading physician scientist in FXS and has been diagnosing and treating FXS for over 30 years and involved in more than 25 clinical trials. She has observed that FXS have a broad spectrum of functional levels especially in cognitive ability and FXS patients with different IQ levels exhibit differential support needs and medication responses. The goal of this project is to derive iPSCs from FXS patients with differential IQ levels and matched controls, therefore we can use these cells to understand the mechanisms underlying these phenotypes and to use these cells for drug testing.”

This project will also bring Zhao and Ashton together as Zhao plans to use RosettaArray® technology, developed by Ashton and licensed by his startup Neurosetta, LLC, as a potential cell culture platform for phenotypic assessment.

“Obtaining funding to derive iPSCs has been highly challenging because this is not considered as hypothesis driven,” says Zhao. “The SCRMC pilot funding allows us to obtain preliminary data and hypothesis for larger funding in the future.”