NEWS

01/2024: Dr. Tarek Magdy has been invited to serve as a study section committee member of the Career Development Award at the American Heart Association.

12/2023: Dr. Tarek Magdy was selected as a research project leader at the NIH/NIGMS Center of Biomedical Research Excellence (COBRE) grant.

08/2023: Dr. Tarek Magdy has been invited to serve as an Early Career Reviewer in the Early Faculty Independence Award at the American Heart Association.

08/2023: Our team member, Sohalia Schoen, won the Best Poster Presentation at the CURIOUS Research Day. Read more on our Team Member section.

06/23: Dr. Tarek Magdy has been invited to serve as an Early Career Reviewer in the Genetics of Health and Disease (GHD) study section at the National Institute of Health.

05/2023: The Magdy laboratory is very excited to welcome Dr. Hilansi Rawat joined the team as a Postdoctoral Fellow. Dr. Rawat completed her M.Sc. in Cardiovascular Science from Georg-August-University, Göttingen, Germany and completed her Ph.D. in 2022 from the Technical University of Munich (TUM), Munich, Germany. 

04/2023: Dr. Tarek Magdy was invited to deliver a talk at AbbVie 2023 Genomics Research Center (GRC) Seminar Series, Chicago.

12/2022: Dr. Tarek Magdy was invited to act as a Topic editor for Frontiers in Pharmacology Sec. Pharmacogenetics and Pharmacogenomics. The topic entitled "Brief research reports in pharmacogenetics and pharmacogenomics"

08/2022: The Magdy Laboratory officially opens its doors at LSU Health Shreveport. Please visit us at the BRI building, room F3-15.

RESEARCH

The Magdy laboratory is trying to understand the role of the genome in patient-specific drug response and disease predisposition. We are particularly interested in the pharmacogenomics of cardio-oncology and cardiovascular diseases using human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). We perform comprehensive genetic studies focusing on identifying and validating novel pharmacogenetic determinants, providing mechanistic explanations for these genetic determinants, and developing a genome-informed drug discovery pipeline. To do this, we adopt state-of-the-art techniques, including somatic cell reprogramming into human induced pluripotent stem cells, multi-lineage iPSC differentiation, CRISPR/Cas9-mediated functional genomics methods, multi-omics approaches, and bioinformatics, combined with various quantitative and qualitative in vitro studies.

Investigating the Pharmacogenomics of Chemotherapy-induced cardiotoxicity using hiPSC-CMs

The cardiotoxicity of certain chemotherapeutic agents is now well-established. It has led to the development of cardio-oncology, increased cardiac screening of cancer patients, and limited patients' maximum cumulative chemotherapeutic dose. The effect of chemotherapeutic regimes on the heart essentially involves cardiomyocyte death, leading to cardiomyopathy and heart failure or the induction of arrhythmias. Of these cardiotoxic drugs, those resulting in clinical cardiotoxicity can range from 8 to 26% for doxorubicin, 7–28% for trastuzumab, or 5–30% for paclitaxel. For tyrosine kinase inhibitors, QT prolongation, arrhythmia, ischemia, and hypertension have been reported in 2–35% of patients.

The genetic rationale for why certain patients experience cardiotoxicity while others can tolerate high chemotherapy doses has proven highly elusive. This has led to significant genomic efforts using targeted and genome-wide association studies (GWAS) to divine the pharmacogenomic cause of this predilection. We use hiPSC-CMs to identify and validate the putative risk and protective role of single nucleotide polymorphisms (SNPs) in relation to chemotherapy-induced cardiotoxicity. 

Two of the most replicated doxorubicin-induced cardiotoxicity-associated loci are SNP rs2229774 in retinoic acid receptor-g (RARG) and SNP rs7853758 in the solute carrier transporter family 28 member 3 (SLC28A3). Firstly, Using CRISPR/Cas9–mediated genetic editing, we validated the GWAS-identified variant rs2229774 in RARG as directly causative in doxorubicin-induced cardiotoxicity (DIC), confirming that heart cells from patients harboring this variant are at higher risk of DIC. We discovered that a small molecule RARG agonist significantly attenuates cardiomyocyte doxorubicin sensitivity in vitro and in vivo, reducing acute murine cardiotoxicity by almost 50%. Further analyses reveal that RARG-associated doxorubicin-induced cardiotoxicity (DIC) risk is mediated via two established mechanisms of cardiotoxicity, direct repression of TOP2B and regulation of ERK phosphorylation mediated cardioprotection, pathways known to lead to downstream modulation of mitochondrial integrity.

In another project, we demonstrate for the first time that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the SLC28A3 locus and that SLC28A3 expression influences the severity of DIC. Using base editing, we pinpointed a novel cardioprotective SNP rs11140490 within the SLC28A3 locus, which exerts its effect by regulating an antisense long noncoding–RNA that we named (SLC28A3-AS1) that overlaps with SLC28A3. Using high–throughput drug screening (n = 1280) in patient-derived cardiomyocytes and whole organism validation in mice, our work identified the SLC competitive inhibitor desipramine as protective against DIC. In summary, our work demonstrates the power of the human induced pluripotent stem cell model to take a single nucleotide polymorphism from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.

Developing novel and cost-effective bioinformatics and experimental approaches to identify causal genetic variants

The genome-wide association study (GWAS) is one of the most used pharmacogenomic approaches and provides positive statistical associations between variants and an investigated phenotype. The vast majority of GWASs depend solely on genotyping chips that capture only hundreds of thousands of SNPs, known as ‘‘tag SNPs’’ that are distributed across the entire genome. Tag SNPs are SNPs in perfect linkage disequilibrium (LD) with many other neighboring SNPs and act as surrogates for their detection. Thus, a statistically significant GWAS hit is always co-inherited (linked) with several other SNPs that have indistinguishable statistical associations with the studied phenotype, leaving us with numerous possibilities to investigate in relation to causality. Owing to this LD issue, GWASs require downstream fine-mapping and further genetic examination at candidate loci to provide more comprehensive information about positive hits and eventually narrow down the list of potential causal SNPs for downstream mechanistic validation. We developed a precise and cost-effective Nanopore sequencing-based pipeline that provides comprehensive and accurate information at candidate loci to identify potential causal single-nucleotide polymorphisms (SNPs). We demonstrate the utility of this technique via the fine-mapping of a GWAS-positive hit comprising a synonymous SNP associated with doxorubicin-induced cardiotoxicity. In this work, we provide a proof of principle for applying Nanopore sequencing in post-GWAS fine-mapping and pinpointing potential causal SNPs with a minimal cost of just ~$10/100 kb/sample.

Unraveling the Role of the Genome in Pediatric Long QT Syndrome variable expressivity

Long QT syndrome (LQTS) is a form of congenital heart disease characterized by delayed repolarization, resulting in an irregular heartbeat, palpitations, cardiac arrest, or sudden cardiac death (SCD). LQTS estimated prevalence is one in every 2,000 individuals. Thus, it is a substantial burden at the population level. Family-based linkage studies have explained the genetic causes of approximately 80% of long QT syndrome (LQTS) cases leaving the cause of the remaining ~20% of cases elusive. These patients do not harbor any known LQTS variants, and thus they likely possess several common SNPs with small effect sizes interacting in an additive manner leading to LQTS. It is statistically infeasible to use family-based linkage or traditional genome-wide association study (GWAS) to discover these remaining genetic causes; therefore, alternative approaches are required. Expression quantitative trait loci (eQTL) analysis has proven to be a powerful tool in variant discovery; this technique is conventionally performed on primary patient samples, comparing gene expression with genotypes without the ability to study differential (i.e., with and without disease) responses. Here, using the human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model, we plan to compare cardiomyocyte gene expression patterns in LQTS patients and controls to discover patient-specific differential eQTL (deQTL). By identifying SNPs that are causative in regulating gene expression in LQTS, we will be able to find highly powered genetic modifiers of the LQTS phenotype and then validate them by genome editing in the hiPSC-CM model. Genetic and functional screening of deQTL-identified LQTS modifiers in unique family members is a novel approach to explain LQTS incomplete penetrance and variable expressivity. This model is exceptionally powerful as it eliminates interpatient variability in disease status, administered drugs, and environmental factors that might affect the LQTS phenotype while maintaining a clear association of the patient’s genetic background with LQTS.

SELECTED PUBLICATIONS

1. Magdy T, Jouni M, Kuo HH, Weddle CJ, Lyra-Leite D, Fonoudi H, Romero-Tejeda M, Gharib M, Javed H, Fajardo G, Ross CJD, Carleton BC, Bernstein D, Burridge PW. Identification of Drug Transporter Genomic Variants and Inhibitors That Protect Against Doxorubicin-Induced Cardiotoxicity. Circulation. 2022. PMID: 34874743.
2. Magdy T, Jiang Z, Jouni M, Fonoudi H, Lyra-Leite D, Jung G, Romero-Tejeda M, Kuo HH, Fetterman KA, Gharib M, Burmeister BT, Zhao M, Sapkota Y, Ross CJ, Carleton BC, Bernstein D, Burridge PW. RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy. Cell Stem Cell. 2021. PMID: 34525346.
3. Huang KM, Zavorka Thomas M, Magdy T, Eisenmann ED, Uddin ME, DiGiacomo DF, Pan A, Keiser M, Otter M, Xia SH, Li Y, Jin Y, Fu Q, Gibson AA, Bonilla IM, Carnes CA, Corps KN, Coppola V, Smith SA, Addison D, Nies AT, Bundschuh R, Chen T, Lustberg MB, Wang J, Oswald S, Campbell MJ, Yan PS, Baker SD, Hu S, Burridge PW, Sparreboom A. Targeting OCT3 attenuates doxorubicin-induced cardiac injury. Proc Natl Acad Sci USA. 2021.PMID: 33495337.
4. Magdy T, Kuo HH, Burridge PW. Precise and Cost-Effective Nanopore Sequencing for Post-GWAS Fine Mapping and Causal Variant Identification. iScience. 2020. PMID: 32203907.
5. Castellino SM, Dreyer ZE, Hudson MM, Robison LL, Magdy T, Blanco JG, Relling MV, Burridge P, Bhatia S. Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children's Oncology Group ALTE03N1 report. Cancer. 2020. PMID: 32413235.
6. Magdy T, Schuldt AJT, Wu JC, Bernstein D, Burridge PW. Human Induced Pluripotent Stem Cell (hiPSC)-Derived Cells to Assess Drug Cardiotoxicity: Opportunities and Problems. Annu Rev Pharmacol Toxicol. 2018. PMID: 28992430.

POSITIONS

Post-doctoral Fellows

We are expanding! A new vacant position for a Post-doctoral Fellow is currently available in our lab to study the genetics of congenital heart defects using induced pluripotent stem cells (iPSC). You will work in a highly supportive and collaborative environment. We will learn, grow and evolve together. Shreveport is a nice, friendly, and affordable place to live in.

To apply:

https://www.lsuhsc.edu/shv/CareerOpportunities/Home/Detail/3993

To enquire about opportunities, contact Dr. Magdy at tarek.mohamed@lsuhs.edu.

Graduate Students
Graduate students interested in conducting research in the Magdy lab should review the current laboratory research directions and contact Dr. Magdy at tarek.mohamed@lsuhs.edu.

Undergraduate Research Assistants
We are not currently hiring any additional undergraduates. However, positions can become available during the summer.

Medical Students, Residents, and Fellows
The Magdy laboratory has several research projects available for any Medical Students, Residents, and Fellows interested in studying the Pharmacogenomics of cardiovascular diseases and Cardio-Oncology.

CONTACT US

LSU Health Shreveport
Department of Pathology and Translational Pathobiology
1501 Kings Highway
Shreveport, LA 71103

Tarek Magdy, PharmB, PhD
Office: BRI F3-15 / Lab: BRI F3-22
Phone: 318-675-8144 (Office)
Email: Tarek.Mohamed@lsuhs.edu

TEAM MEMBERS

1. Hilansi Rawat, PhD

Postdoctoral Fellow

Email: hilansi.rawat@lsuhs.edu

Dr. Hilansi Rawat received her B.Sc. in Biotechnology (Bachelor of Science) in 2015 from Banasthali University, India. In 2017, Dr. Rawat completed her M.Sc. in Cardiovascular Science from Georg-August-University, Göttingen, Germany. During her time in Göttingen, she worked in the lab of Prof. Dr. Katrin Streckfuß-Bömeke and developed a keen interest in iPSCs (induced pluripotent stem cells). Dr. Rawat completed her PhD in 2022 from the Technical University of Munich (TUM), Munich, Germany.

2. Tasneem Abdulrahman

PhD Candidate

Tasneem graduated from Cairo University, Egypt, in 2017 with a B.Pharm. in Clinical Pharmacy. She received her M.Sc. in Cancer Biology and Therapeutics in 2022 from Cardiff University, UK. Her Master's thesis pertained to FAK overexpression and activity in metastatic triple-negative breast cancer. Tasneem's current projects in the lab focus on understanding the role of the genome in MASH using hiPSC-derived hepatocytes. Additionally, she is investigating the mechanisms of Trastuzumab-induced cardiotoxicity using hiPSC-derived cardiomyocytes.

3. Sohalia Schoen 

Undergraduate Student

I would like to congratulate Sohalia Schoen for winning the Best Poster Presentation at the Cardiovascular Undergraduate Research Initiative fOr Underrepresented Students (CURIOUS) Research Day. Sohalia is a smart undergraduate student in our lab. Huge thanks to Hilansi Rawat, PhD!

4. Ashtyn Phillippi  

Medical Student

Ashtyn Phillippi received her Bachelor of Science degree in Microbiology in 2023 from Auburn University. During her time at Auburn, she was a part of a pharmacogenomics lab where she studied the variation in response to chemotherapeutic drugs for multiple myeloma and prostate cancer. She is currently a first-year medical student with a passion for cardiology and wants to learn more about chemotherapy-induced cardiotoxicity.

5. Majeed Al-Quraishi, MD

Pathology Resident, PGY-1
Email: Majeed.Alquraishi@lsuhs.edu