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Mitochondrial Disease, ALL, Type 2 Diabetes, Sleep Apnea

Published on September 16, 2022 in Cornerstone Blog · Last updated 5 months 3 weeks ago


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In the News

The temperature may be dropping here in Philadelphia, but scientific inquiry at the Research Institute continues at a feverish pace. In this week's news roundup, learn about preliminary research of a potential therapeutic option for a rare and aggressive form of mitochondrial disease. Read on to find out more about the genomic landscape of acute lymphoblastic leukemia, a series of causal genes implicated in driving the risk for type 2 diabetes, and genetic risk factors for sleep apnea in children.

Hakon Hakonarson, MD, PhD

Hakon Hakonarson, MD, PhD

Multiple Genetic Risk Markers for Pediatric Sleep Apnea Identified

Multiple genes are implicated in pediatric obstructive sleep apnea (OSA), according to findings by researchers from the Center for Applied Genomics at CHOP. The researchers also distinguished genes that are associated with sleep apnea risk in males vs. females, as well as in those with European vs. African ancestry. Prior to this study, no genome-wide association study had been performed to determine whether genetic causes existed.

OSA is a sleep-related breathing disorder that can cause a child to stop breathing while they are sleeping, usually due to a blockage in the airway. The disorder affects between 1% and 5% of all children and most commonly develops when children are between 2 and 6 years old, though it can occur at any age.

The researchers developed an algorithm that assessed 1,486 patients, of whom 53.7% were African American, and the rest were of European ancestry. The findings appeared in the journal Sleep.

"This study emphasizes the importance of study populations with diverse ethnic backgrounds to identify unique and shared genetic markers that contribute to the heterogeneity of obstructive sleep apnea in children," said Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics. "We expect that further studies with larger samples are likely to identify more genetic markers that together may support the development of novel therapies for the disorder."

Learn more in the CHOP press release.

Marni Falk, MD

Marni Falk, MD

Researchers Investigate Novel Therapeutic Options for Rare and Aggressive Form of Mitochondrial Disease

Researchers at CHOP discovered a molecule with therapeutic potential for children with a rare and severe form of mitochondrial disease caused by a variant in the FBXL4 gene. Since discovering the gene a decade ago, the research group has been striving to find an intervention of true therapeutic value.

This form of mitochondrial disease, which affects multiple systems in the body, disrupts the mitochondrial respiratory chain complex that converts oxygen and nutrients into energy, while causing a buildup of lactic acid. The new findings appear in JCI Insight.

"These are typically very sick children," said Marni Falk, MD, executive director of the Mitochondrial Medicine Frontier Program at CHOP and professor of Pediatrics and the University of Pennsylvania. "This study is truly the culmination of translating basic research into clinically relevant findings that represent an enormous breakthrough in how we might be able to improve the health of these patients, along with the breadth of cellular effects that treatment may have."

The researchers evaluated 12 potentially therapeutic options and tested their effectiveness in a C. elegans model with FBXL4 gene pathogenic variants. Among the drug candidates, dichloroacetate (DCA) demonstrated clear beneficial effects. The researchers then performed validation studies in a zebrafish model and in human fibroblast cell lines. In these models, DCA prevented stressor-induced brain death, impairment of neurological and muscular functions, mitochondrial dysfunction, and other stressor-induced mitochondrial defects.

"With no other approved options, we believe our positive findings regarding DCA for the treatment of FBXL4 mitochondrial disease should lead to its rigorous clinical study in human patients," said Manuela Lavorato, PhD, a research assistant professor at the University of Pennsylvania School of Medicine and the Mitochondrial Medicine Frontier Program and first author of the study.

Find out more in the CHOP press release.

Stephen P. Hunger, MD

Stephen P. Hunger, MD

Genomic Landscape of Acute Lymphoblastic Leukemia Mapped by Research Team

A multi-institutional group of pediatric cancer researchers, including investigators from CHOP, have characterized the genomic landscape for acute lymphoblastic leukemia (ALL), identifying the number and type of recurrently altered genes that drive ALL and its outcomes. ALL is the most common pediatric cancer.

"This study breaks new ground in terms of defining the many different genetic subtypes of ALL, several of which were newly discovered as a result of this research," said co-senior author Stephen P. Hunger, MD, chief of the Division of Oncology and director of the Center for Childhood Cancer Research at CHOP. "By identifying a broad landscape of mutations that are implicated in ALL, we now have new targets and pathways we can try to exploit to improve cure rates and reduce negative treatment side effects."

The researchers analyzed samples from 2,754 children, adolescents, and young adults with newly diagnosed B-ALL or T-ALL using whole exome, whole genome, and transcriptome sequencing, as well as single nucleotide polymorphism array. They identified 376 potential cancer driver genes, of which 70 had not been previously implicated in ALL. Of those 70, 43 had been implicated previously in other solid tumors or blood tumors, and the remaining 27 had not been reported in human cancer. The findings appear in Nature Genetics.

Check out the CHOP press release for more.

Andrew D. Wells, PhD

Andrew D. Wells, PhD

3D Mapping Techniques Help Researchers Implicate Series of Genes as Drivers of Type 2 Diabetes Risk

CHOP researchers identified multiple genetic variants and corresponding gene pairing in the pancreas that are implicated in type 2 diabetes. The resulting datasets will be a key resource for researchers to delve further into the genetic origins of type 2 diabetes. The findings appeared in Cell Metabolism.

"Without an accurate map of how genes are folded together in a cell, you're essentially guessing the role that these genetic variants play," said Andrew D. Wells, PhD, associate professor of Pathology and Laboratory Medicine and co-director of the Spatial and Functional Genomics Collaborative at CHOP. "In this study, we applied three-dimensional mapping techniques to chromosomes of highly relevant cell types, which allowed us to identify a series of genes that have never been implicated before in type 2 diabetes."

Dr. Wells was a senior author on the paper along with Struan F.A. Grant, PhD, also co- director of the Spatial and Functional Genomics Collaborative. The researchers created 3-D epigenomic profiles of purified acinar, alpha, and beta cells in the human pancreas using several techniques that examined them at the single-cell level. They identified a series of causal variants and target gene pairs at 194 different type 2 diabetes signals using the 3-D chromatin maps. They also found that alpha and acinar cells appear to play a greater role in type 2 diabetes than previously thought.

Check out the CHOP press release for more.


Catch up on our headlines from our September 2 In the News:

  • CHOP, Penn Launch Kidney Innovation Center to Improve Treatment Across the Lifespan
  • Study Supports Depression Screening as Regular Component of Concussion Care
  • First Potentially Curative Gene Therapy for Beta Thalassemia Approved by FDA
  • Researchers Study Form of Vitamin B3 and Exercise Intolerance in Mitochondrial Impairment

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