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Associate Investigator

Molecular Genetics Section

Education

B.S., The George Washington University

Ph.D., University of Groningen

Biography

Dr. Erdos focuses on translational research determining the effect of genetic variation on gene function and identifying primary targets for potential therapeutic development. Prior to arriving at the National Institutes of Health, Dr. Erdos studied circulating thymic peptides modulated by immune disorders and HIV at the George Washington University. Dr. Erdos moved to the National Heart, Lung and Blood Institute in 1990 where he focused on IL2 receptor-associated kinase signaling and the search for the IL2Rg gene. In 1993, he moved to the NHGRI Intramural Research Program where he focused initially on the discovery and functional analysis of the BRCA1 gene.

Currently, Dr. Erdos conducts preclinical translational research to identify and validate potential therapeutics for the rare premature-aging disease, Hutchinson Gilford Progeria Syndrome (HGPS). Two of those treatment strategies are in the application process for FDA approval. In the context of complex genetic disease, Dr. Erdos is using multi-omics analyses to elucidate the impact and functional basis of risk variants for type 2 diabetes (T2D). That information can both provide predictive risk for disease prevention and point to optimal targets for development of potential therapeutic agents. It was that work on T2D that led to the awarding of his Ph.D. from the University of Groningen.

The T2D project is highly collaborative. Dr. Erdos is a senior investigator in the Finnish US Investigation of NIDDM (FUSION), non-insulin dependent diabetes mellitus (NIDDM) genetics study and in the Integrated Network for Systematic Analysis of Pancreatic Islet RNA Expression (InsPIRE) consortium. In addition, he is a collaborator in the Accelerating Medicines Partnership in Type 2 Diabetes (AMP-T2D) consortium.

Scientific Summary

The application of genetic, genomic and functional biology approaches are valuable and increasingly powerful ways to provide understanding of both rare and complex diseases and of the potential for therapeutic development.

Hutchinson-Gilford Progeria Syndrome

In the ultra-rare premature aging disorder HGPS, Dr. Erdos and colleagues' lab discovered the dominant negative cryptic splice mutation, c.1824 C/T, in the LMNA gene generates the mutant progerin protein responsible for HGPS and causes a plethora of phenotypic consequences, including death from heart attack of stroke by the early teens. But there is also much hope. In fact, HGPS can be seen as a textbook demonstration of the evolution of therapeutic advances for a rare disorder. Normally, the LMNA gene precursor protein, prelamin A, is farnesylated prior to incorporation into the nuclear membrane, then cleaved by an endoprotease to release mature lamin A that is incorporated in the nuclear lamina matrix. The deletion of the 50 amino acids in the mutant progerin protein created by the cryptic splice mutation results in the permanent farnesylation of mature lamin A causing disruption of nuclear organization and chromatin structure. The cellular consequence is premature senescence, which contributes to the accelerated aging phenotype.

Because this mutation directs a dominant negative effect, it facilitated the generation of a humanized transgenic mouse model by inserting a human genomic DNA segment containing the LMNA gene engineered with the c.1824C/T mutation. In the heterozygous state the mouse model embodies the characteristic vascular defects found in HGPS patients, including age-related loss of vascular smooth muscle cells (VSMCs) and stiffening of arterial walls. In the homozygous state the mouse presents with many additional phenotypes characteristics of HGPS including retarded growth, lipodystrophy, joint contractures and premature death at a median of 210 days.

 

LMNA progerin illustration

 

The HGPS mouse is a highly useful model for preclinical investigation of potential therapeutics, particularly for genetic therapies, because the effects are derived from the expression of progerin from human LMNA DNA sequence.

In the realm of small molecule therapeutics, farnesyl transferase inhibitors (FTIs) target the specific defect in progerin that generates the dominant negative cytotoxic effect. Dr. Erdos and colleagues reasoned that blocking the permanent addition of the farnesyl hydrophobic tail would reduce the deleterious effects of the mutant progerin protein. Treating the mouse model with FTIs was successful at reducing the cardiovascular defects in young mice. In addition, it improved the cardiovascular histopathology when administered to older mice. This work supported the first clinical trial application for the use of FTIs to treat children with HGPS, conducted by collaborators at Boston Children’s Hospital. That trial showed improvement in arterial stiffness, and ultimately a modest extension in lifespan. FDA approved lonafarnib (a farnesyltransferase inhibitor) for HGPS in 2021.

In a complementary approach, the hypothesis that rapamycin analogues, capable of inhibiting the mTOR pathway, would reduce the deleterious effects of progerin by stimulating cellular autophagy was tested in the mouse model. Treatment of the HGPS mouse model with rapamycin resulted in improved cardiovascular histopathology and moderately increased survival. These results were validated by crossing the mouse model with an mTOR hypomorphic genetic mouse model provided by Dr. Toren Finkel, exhibiting reduced mTOR expression achieved similar benefits. A trial of the rapalog everolimus, combined with lonafarnib, is currently underway.

In a more direct effort to target the genetic cause of HGPS, Dr. Erdos and colleagues are employing antisense oligomer splice inhibition therapeutics to reduce progerin production at the mRNA level by blocking the mutant splice site. Treatment of the homozygous mouse model with the c.1824 C/T mutation specific peptide-conjugated phosphorodiamidate morpholino-oligomer (PPMO), SRP-2001, improved the cardiovascular state and increased the lifespan of the homozygous mouse model by 62%. Dr. Erdos and colleagues are now supporting the Progeria Research Foundation application with the FDA for treatment of HGPS children with antisense oligomers.

Antisense oligomer therapeutics are safe and more effective than the current small molecule therapeutics (FTIs and rapamycin), but the treatment regimen requires frequent injections for the lifetime of the patient. More recently, the laboratory of Dr. David Liu at the Broad Institute has developed the CRISPR-mediated Adenine-deaminase DNA Base Editor (ABE) packaged in adeno-associated virus (AAV9) customized for the c.1824C/T mutation. This requires only a single intravenous administration, a perfect candidate for therapeutic development for HGPS. In collaboration with the Liu laboratory, Dr. Erdos and colleagues have shown that the AAV9-ABE-c.1824 C/T DNA base editors are capable of systemic delivery in mice and can achieve 8-30% mutation correction in critical HGPS tissues. Somatic selection further provides an advantage – as the uncorrected cells senesce, the corrected cells seem to take their place: six months post treatment the large arteries are fully populated with VSMCs negative for progerin staining. In a longevity trial the treated mice achieve a 2.4-fold increase in lifespan. Dr. Erdos is now collaborating on the development of ABEs for FDA application by Beam Therapeutics and the Progeria Research Foundation.

 

Movat Stain and H&E Stain

 

Type 2 Diabetes

Type 2 diabetes is a complex multi-organ system disorder characterized by dysregulation of glucose and fatty acid sensing and synthesis in the liver, insulin resistance in the adipose and muscle, and ultimately failure to compensate for high blood sugar by insulin secretion from the pancreatic islets. Complex diseases like T2D present a formidable challenge for translational research into potential therapeutics. Although there is an established genetic component underlying T2D susceptibility, environmental conditions such as diet and physical activity are a significant contribution to the prevalence of T2D in populations. Based on work by Dr. Erdos and colleagues' group and others, there are over 400 genetic variants significantly associated with T2D. Over 90% of these fall in non-coding regions of the genome, making it difficult to determine what gene has its expression influenced by the variant. Dr. Erdos’s T2D research currently focuses on the development of functional genomics analyses of model systems to determine the causal effect of T2D associated variants, identify the target genes associated with the variants and define their role in the etiology of T2D.

Dr. Erdos is the lead scientist in the FUSION tissue biopsy project which aims to investigate tissue specific effects of T2D associated variants on the critical tissues involved in T2D. The FUSION study collected plasma, muscle and adipose from normal glucose tolerant (NGT) subjects, impaired glucose tolerant (IGT) and newly diagnosed T2D subjects not on medication from the Finnish population in order to perform transcriptomics, epigenomics and gene-environment interaction analyses correlated with T2D associated variants. In addition, skin biopsies were obtained from each subject for fibroblast cell culture and induced pluripotent stem cell (iPSC) generation, with the goal to differentiate the iPSCs into tissues for functional investigation of T2D associated variants. To complement the tissues accessible from FUSION subjects, Dr. Erdos has been collecting pancreatic islets and liver tissue from cadaveric tissue distribution organizations in order to enable complementary T2D variant analyses in organ systems important in T2D but not attainable from the FUSION subjects. The aim of these studies is to compile the knowledge gained from studying these multi-organ genetic associations to classify subtypes of T2D for the identification of potential therapies based on the class of diabetes presented.

 

Disease-Relevant Tissues

 

The primary pancreatic islet model system Dr. Erdos is developing is the automated differentiation of induced pluripotent stem cells (iPSCs) into mature pancreatic beta cells, carried out in collaboration with the automation experts at the New York Stem Cell Foundation. Dr. Erdos selected 52 individuals from the FUSION Tissue Biopsy Study, either normal glucose tolerant, impaired glucose tolerant or newly diagnosed untreated T2D subjects, and is examining the differentiation activity of these lines using single-cell multi-omic integrated analysis of chromatin structure and gene expression with glucose stimulated insulin secretion (GSIS) functional analysis. The cell state and functional consequence are integrated with genotype and polygenic risk to investigate the functional impact of T2D-associated variants and identify potential targets for focused therapeutic development. For known causal variants Dr. Erdos and colleagues are also able to employ CRISPR-based DNA editing to create isogenic iPSC lines for allelic evaluation using this automated system. In addition, Dr. Erdos and colleagues are employing this system in CRISPRi -genome wide gene inhibition experiments to identify critical genes required for development and maturity of pancreatic beta cells and functional response to glucose and insulin secretagogues. Their ultimate goal is to determine the most promising target genes in these T2D functional networks for the development of precision therapeutics.

Publications

Koblan LW, Erdos MR, Wilson C, Cabral WA, Levy JM, Xiong ZM, Tavarez UL, Davison L, Gete YG, Mao X, Newby GA, Doherty SP, Narisu N, Sheng Q, Krilow C, Lin CY, Gordon LB, Cao K, Collins FS, Brown JD, Liu DR. In Vivo Adenine Base Editing Rescues Hutchinson-Gilford Progeria Syndrome. Nature. 2021 Jan;589(7843):608-614. doi: 10.1038/s41586-020-03086-7.

Erdos MR, Cabral WA, Tavarez UL, Gvozdenovic-Jeremic J, Narisu N, Zerfas PM, Crumley S, Boku Y, Hanson G, Mourich DV, Kole R, Eckhaus MA, Gordon LB, Collins FS. A targeted antisense-based approach to inhibit progerin production demonstrates the in vivo therapeutic potential of morpholinos for Hutchinson-Gilford progeria syndrome. Nat Med. 2021 Mar;27(3):536-545. doi: 10.1038/s41591-021-01274-0.

Cabral WA, Tavarez UL, Beeram I, Yeritsyan D, Boku Y, Eckhaus MA, Nazarian A, Erdos MR, Collins FS. Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson-Gilford Progeria syndrome. Aging Cell. 2021 Sep;20(9):e13457. doi: 10.1111/acel.13457.

Viñuela A, Varshney A, van de Bunt M, Prasad RB, Asplund O, Bennett A, Boehnke M, Brown AA, Erdos MR, Fadista J, Hansson O, Hatem G, Howald C, Iyengar AK, Johnson P, Krus U, MacDonald PE, Mahajan A, Manning Fox JE, Narisu N, Nylander V, Orchard P, Oskolkov N, Panousis NI, Payne A, Stitzel ML, Vadlamudi S, Welch R, Collins FS, Mohlke KL, Gloyn AL, Scott LJ, Dermitzakis ET, Groop L, Parker SCJ, McCarthy MI. Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D. Nat Commun. 2020 Sep 30;11(1):4912. doi: 10.1038/s41467-020-18581-8. 

Taylor DL, Jackson AU, Narisu N, Hemani G, Erdos MR, Chines PS, Swift A, Idol J, Didion JP, Welch RP, Kinnunen L, Saramies J, Lakka TA, Laakso M, Tuomilehto J, Parker SCJ, Koistinen HA, Davey Smith G, Boehnke M, Scott LJ, Birney E, Collins FS. Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle. Proc Natl Acad Sci U S A. 2019 May 28;116(22):10883-10888. doi: 10.1073/pnas.1814263116.

Lawlor N, Márquez EJ, Orchard P, Narisu N, Shamim MS, Thibodeau A, Varshney A, Kursawe R, Erdos MR, Kanke M, Gu H, Pak E, Dutra A, Russell S, Li X, Piecuch E, Luo O, Chines PS, Fuchbserger C; NIH Intramural Sequencing Center, Sethupathy P, Aiden AP, Ruan Y, Aiden EL, Collins FS, Ucar D, Parker SCJ, Stitzel ML. Multiomic Profiling Identifies cis-Regulatory Networks Underlying Human Pancreatic β Cell Identity and Function. Cell Rep. 2019 Jan 15;26(3):788-801.e6. doi: 10.1016/j.celrep.2018.12.083.

DuBose AJ, Lichtenstein ST, Petrash NM, Erdos MR, Gordon LB, Collins FS. Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts. Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4206-4211. doi: 10.1073/pnas.1802811115. Erratum in: Proc Natl Acad Sci U S A. 2018 Apr 16.

Varshney A, Scott LJ, Welch RP, Erdos MR, Chines PS, Narisu N, Albanus RD, Orchard P, Wolford BN, Kursawe R, Vadlamudi S, Cannon ME, Didion JP, Hensley J, Kirilusha A; NISC Comparative Sequencing Program, Bonnycastle LL, Taylor DL, Watanabe R, Mohlke KL, Boehnke M, Collins FS, Parker SC, Stitzel ML. Genetic regulatory signatures underlying islet gene expression and type 2 diabetes. Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):2301-2306. doi: 10.1073/pnas.1621192114. 

Scott LJ, Erdos MR, Huyghe JR, Welch RP, Beck AT, Wolford BN, Chines PS, Didion JP, Narisu N, Stringham HM, Taylor DL, Jackson AU, Vadlamudi S, Bonnycastle LL, Kinnunen L, Saramies J, Sundvall J, Albanus RD, Kiseleva A, Hensley J, Crawford GE, Jiang H, Wen X, Watanabe RM, Lakka TA, Mohlke KL, Laakso M, Tuomilehto J, Koistinen HA, Boehnke M, Collins FS, Parker SC. The genetic regulatory signature of type 2 diabetes in human skeletal muscle. Nat Commun. 2016 Jun 29;7:11764. doi: 10.1038/ncomms11764. 

Parker SC, Stitzel ML, Taylor DL, Orozco JM, Erdos MR, Akiyama JA, van Bueren KL, Chines PS, Narisu N; NISC Comparative Sequencing Program, Black BL, Visel A, Pennacchio LA, Collins FS; National Institutes of Health Intramural Sequencing Center Comparative Sequencing Program Authors; NISC Comparative Sequencing Program Authors. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl. Acad. Sci., U S A. 2013 Oct 29;110(44):17921-6. 

Cao K, Graziotto JJ, Blair CD, Mazzulli JR, Erdos MR, Krainc D, Collins FS. Rapamycin reverses cellular phenotypes and enhances mutant protein clearance in Hutchinson-Gilford progeria syndrome cells. Sci Transl Med. 2011 Jun 29;3(89):89ra58.

Stitzel ML, Sethupathy P, Pearson DS, Chines PS, Song L, Erdos MR, Welch R, Parker SC, Boyle AP, Scott LJ; NISC Comparative Sequencing Program, Margulies EH, Boehnke M, Furey TS, Crawford GE, Collins FS. Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metab. 2010 Nov 3;12(5):443-55.

Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, Conneely KN, Qu X, San H, Ganesh SK, Chen X, Avallone H, Kolodgie FD, Virmani R, Nabel EG, Collins FS. A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model. Proc. Natl. Acad. Sci., U S A. 2008 Oct 14;105(41):15902-7.

Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003 May 15; 423(6937):293-8

Full Bibliography 

Last updated: April 5, 2022