Clinical Research Achievements

Acute myeloid leukemia (AML) treatment remains challenging due to significant cellular heterogeneity within and between patients. While traditional classification relies on morphology and limited surface markers, single-cell RNA sequencing enables precise determination of leukemia cell states using thousands of gene expression features. Understanding how genetic mutations disrupt normal blood cell development could improve therapeutic targeting. Methods: Researchers constructed a comprehensive single-cell reference atlas of human bone marrow hematopoiesis from 263,159 single-cell transcriptomes spanning 55 cellular states across 45 healthy donors. They then mapped more than 1.2 million cells from 318 leukemia samples onto this reference to identify patterns of aberrant differentiation. The team also analyzed bulk RNA-seq data from 1,224 AML patients to link genetic alterations with specific differentiation states. Results: The analysis revealed 12 recurrent patterns of aberrant differentiation in AML, ranging from early stem cell blocks to mature myeloid accumulation. Notably, the study identified unexpected AML cell states resembling lymphoid and erythroid progenitors that were prognostic within normal karyotype AML. Systematic mapping revealed specific differentiation landscapes associated with more than 45 genetic drivers, showing how different mutations corrupt distinct stages of blood cell development. Conclusions: This work demonstrates that precise mapping of malignant cell states provides insights into leukemogenesis and refines disease classification. The identification of lymphoid- and erythroid-like states in AML challenges traditional diagnostic boundaries and reveals new prognostic markers independent of genetic classifications. The publicly available BoneMarrowMap resource enables researchers to rapidly classify leukemia cells and could facilitate more personalized treatment approaches based on cellular differentiation patterns rather than genetics alone. Paper and research by Andy Zeng and larger team at the University of Toronto

The Stanford Medicine study developed stem cell-derived heart tissues to investigate tachycardia’s effects. Researchers, led by Joseph Wu, created over 400 heart tissue samples to understand how rapid heart rates impact the body. They discovered that the heart’s energy source shifts from fats to sugars in response to oxygen shortage during tachycardia. By supplementing these tissues with NAD, a vital molecule, they observed quicker recovery of heart function. This research aligns well with clinical human data and canine models, offering a promising non-animal model for studying cardiac conditions and testing therapeutics. For a detailed review, you can visit the article here. In terms of practical applicability, the study marks a significant advancement in understanding and potentially treating tachycardia-induced cardiomyopathy. By utilizing human stem cell-derived tissues, the research provides a more accurate model of human heart behavior under stress conditions like tachycardia. This approach is a substantial improvement over traditional in vitro studies, as it mimics the actual in vivo environment more closely. The potential for rapid recovery observed with NAD supplementation opens new avenues for therapeutic interventions. These findings could lead to more effective treatments and improved patient outcomes, particularly in diagnosing and managing tachycardia-related heart issues. https://lnkd.in/gstsAY3E

In years gone by, many patients in their 80’s trying to live their best lives were told that their only option for their #mitral valve disease was to go home and consider hospice care. Fast forward to 2024. Life altering TEER valve repair technology (Abbott #Mitraclip in this case, Edwards Lifesciences #Clasp an option in others) when used in appropriate situations, combined with real time 3D echo imaging (Philips Imaging in this case) and even futuristic applications of fusion technology have changed the game even in very complex cases. This case is an example of how in our labs UAB Medicine we routinely apply these technologies to the toughest cases such as this complex commissural flail in a previously very independent active patent in their mid-80’s with NYHA class 4 heart failure who was told hospice was their only option. Application of expertise, experience and technology allowed this patient's valve to be repaired, them to be up and walking within hours without symptoms, and home the next morning to embrace a new lease on life with their family. If you had told me 15 years ago that this complex commissural flail repair procedure could be done trans-catheter, never mind take us only 30 minutes and the access site in the groin barely recognizable the next day, I would have never believed it. The plethora of exciting mitral repair and replacement options currently in trial (Abbott , Medtronic , Edwards Lifesciences and others) could help countless patients in need of these therapies. The near future is bright for those with mitral valve disease felt not the best candidates for surgery. #healthcare #technology Superfellows Ali Ebrahimi & Madhura Myla Outstanding help in the case! Garima Arora Mouhamed Amr Sabouni Hassan Alkhawam Baran Aksut Phillip Smith Paul M. Khait Alexander Haak Heather White Amy Woodard Michael Dove Amr Salama Dustin Wallace Robby Hendrix Bill Shields

New work from our team published this week in Nature Genetics led by Dr.med. Bruna Gomes. We developed a deep learning system to extract cardiac flow from tens of thousands of cardiac MRIs performed as part of the UK Biobank. We used this framework to determine the genetic basis of cardiac forward flow (the output of the heart) and reverse flow (what happens when valves leak). This is a better way to represent heart function than the commonly used "ejection fraction" that ignores both the size of the heart and leaking valves. Using causal inference we demonstrate the connection between the genetic determinants of the structure of the aorta and the regurgitation of the aortic valve. We hope this work will inspire new approaches both to the optimization of heart function and to the early detection and treatment of aortic valve disease. https://lnkd.in/gfzeatch

In vivo hematopoietic stem cell modification by mRNA delivery Hematopoietic stem cells (HSCs) are the source of all blood cells over an individual’s lifetime. Diseased HSCs can be replaced with gene-engineered or healthy HSCs through HSC transplantation (HSCT). However, current protocols carry major side effects and have limited access. We developed CD117/LNP–messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA and is targeted to the stem cell factor receptor (CD117) on HSCs. Delivery of the anti–human CD117/LNP–based editing system yielded near-complete correction of hematopoietic sickle cells. Furthermore, in vivo delivery of pro-apoptotic PUMA (p53 up-regulated modulator of apoptosis) mRNA with CD117/LNP affected HSC function and permitted nongenotoxic conditioning for HSCT. The ability to target HSCs in vivo offers a nongenotoxic conditioning regimen for HSCT, and this platform could be the basis of in vivo genome editing to cure genetic disorders, which would abrogate the need for HSCT. https://lnkd.in/ggGU_EQy

Two recent breakthrough studies demonstrated that engineering epitopes on donor hematopoietic stem and progenitor cells (HSPCs) used in bone marrow transplants can give hematopoietic lineages selective resistance to monoclonal antibodies or chimeric antigen receptor (CAR) T cells without changing protein regulation or function: Pietro Genovese's team at Dana-Farber Cancer Institute generated base editing of specific genes in HSPCs, such as FLT3, CD123, and KIT, changed epitope markers without altering the normal function of the genes and showed the edited epitope cells resulted in the loss of specific antibody binding sites, making cells resistant to CAR T-cells and monoclonal antibodies without affecting their physiological expression, regulation, and intracellular signaling. (Casirati, G., Cosentino, A., Mucci, A. et al. Nature (2023). Publication Link: https://lnkd.in/eNCq25ps) Saar Gill's and Carl June's teams at the University of Pennsylvania showed CD45 epitope-edited hematopoietic stem cells (HSCs) were protected from anti-CD45-CAR T cells and, unlike CD45 knockout cells, could engraft, persist, and differentiate in vivo; and Epitope edited CD45 CAR T cell were fratricide-resistant and effective against patient-derived acute myeloid leukemia, B cell lymphoma, and acute T cell leukemia. (Wellhausen et al., Sci. Transl. Med. (2023) Publication Link: https://lnkd.in/eWbvGn68)

Fascinating new paper reveals a gut microbiome connection to heart disease. Microbes produce imidazole propionate (ImP), which directly triggers atherosclerosis through immune activation - even without high cholesterol. This microbial metabolite binds to specific receptors on immune cells, causing inflammation and plaque formation. The discovery opens new paths for early detection and targeted therapies based on our microbiome signatures. https://lnkd.in/gJCE4Enz

📢 Research Update: New Findings on Alcohol and Heart Health 🌟 🎉 Congrats to Sinclair Carr, Dana Bryazka, Susan McLaughlin, and team for their work on "A burden of proof study on alcohol consumption and ischemic heart disease" published today in Nature Communications. 📚 This study tackles the complex relationship between alcohol consumption and the risk of ischemic heart disease (IHD). It offers a comprehensive re-evaluation of existing data, aiming to clarify the effects of alcohol on heart health using innovative meta-analytical techniques. 📊 Methodology: Employing the burden of proof meta-analytical framework, the team scrutinized data from cohort, case-control, and Mendelian randomization (MR) studies, encompassing evidence from 1970 to 2021. 🔑 Key Insights: Contrasting Observations: While cohort and case-control studies suggest that low to moderate alcohol consumption is associated with a lower risk of IHD, MR data show no relationship between alcohol and IHD. Methodological Challenges: The study highlights the need to advance MR methodologies and to mimic the design of randomized trials using observational databases to overcome data biases that can distort the estimation of alcohol's impact on IHD. Health Policy Implications: These findings underline the complexity and uncertainty of alcohol's effects on heart health, suggesting that low and moderate drinking does not universally confer benefits and may depend on individual health profiles and consumption patterns. 🌍 Impact: This research underscores the necessity for refined health guidelines regarding alcohol consumption, tailored to individual risk profiles and broader public health contexts. 👏 Funding: This research was supported by the Bill & Melinda Gates Foundation. 🔗 Access the full article here: https://lnkd.in/g6ycwUiR. #️⃣ #HeartHealth #AlcoholConsumption #PublicHealth #NatureCommunications 🗓️ Published online May 14, 2024, this analysis provides a critical perspective on the ongoing debate over alcohol's impact on heart health, guiding future research and policy.

While RNA molecules' effects on hematopoietic tumor cells remained elusive due to delivery challenges, a recent study has made significant headway. Here's what you need to know: 1️⃣ The study explored a novel glucose-attached reversibly ionic oligonucleotide-based nanoparticle (RION) designed to carry a chemically modified miR143-3p, aptly named miR143#12 (named Glu-RION-miR143#12). The nanoparticles are created by self-assembly involving base hybridization and electrostatic interaction via a functionalized chemically modified passenger strand. 2️⃣ Targeted Silencing: This delivery mechanism effectively introduced miR143#12 into hematopoietic tumor cells, silencing not just RAS but a broader network including Sos-1, Akt, ERK1/2, and ERK5. The result? Induced cell cycle arrest and promotion of apoptotic cell death. 3️⃣ Antiproliferative Action: The manner in which miR143#12 hindered the proliferation of hematopoietic tumor cells mirrored its effect on colon cancer KRAS-mutant DLD-1 cells. Most importantly, this action was exclusive to malignant cells, sparing non-malignant cells like human peripheral lymphocytes. The study shows that Glu-RION-miR143#12 holds remarkable promise as a nucleic acid medication, not just for primary hematologic malignancies but also for recurrent malignant hematopoietic cells with RAS mutations. 🔗 https://lnkd.in/edFsfczT #HematopoieticTumor #RNATherapy #CancerResearch #InnovationInMedicine #nanotechnology #nanoparticles #nanomaterials #nano

Stem Cell Therapy 2.0: Harnessing the Power of Mitochondrial Autophagy The article discusses a recent study explaining how mitochondrial transfer therapy restores damaged heart muscle function. Researchers at Boston Children's Hospital found that transferring small amounts of mitochondria from a patient's healthy skeletal muscle cells to their damaged heart muscle cells can significantly improve heart function and help wean children off ECMO (extracorporeal membrane oxygenation) after congenital heart disease or ischemia-reperfusion injury. The study's findings are truly groundbreaking. Contrary to previous assumptions, the transferred mitochondria don't directly power the heart cells. Instead, they initiate a process called autophagy, where the heart cells break down and recycle their underperforming mitochondria. This leads to a more robust pool of mitochondria within the cells, enhancing their energy production and overall fitness. The researchers are now delving into ways to optimize this therapy, such as engineering off-the-shelf mitochondria or directly triggering the autophagy pathways without transplanting mitochondria. The practical implications of this therapy in cardiac transplantation, particularly for donor hearts after circulatory death (DCD), are immense. These hearts often suffer from ischemic damage. The potential of mitochondrial transfer to preserve and enhance the function of these hearts post-transplantation is a beacon of hope in the field of regenerative medicine. This research represents a significant advancement in stem cell therapy and regenerative medicine, as it provides a new understanding of how mitochondrial transfer works and opens up possibilities for optimizing and expanding its use in various heart conditions. The future of stem cell therapy is poised to be shaped by groundbreaking approaches that harness the body's innate regenerative mechanisms. Mitochondrial transfer therapy stands as a shining testament to the potential of stem cell-based therapies. It demonstrates how we can harness the power of cellular rejuvenation and repair without necessarily relying on direct cell replacement or integration. This innovative approach could herald a new era of more effective and widely applicable regenerative therapies, transcending the boundaries of heart disorders. We will hear and see much more about this. JP https://lnkd.in/eK_AgTwd