Biology subjects

Mohamed, A. O.

Publications and source records attributed to Mohamed, A. O..

4 recordsLinked to original sources

bioRxiv2025

A Combinatorial mRNA Therapy for Treating Rheumatoid Arthritis and Osteoarthritis by Inhibiting Inflammation and Promoting Cartilage Regeneration

Rheumatoid arthritis (RA) and osteoarthritis (OA) are debilitating joint disorders with distinct etiologies but share common pathological features of chronic inflammation and progressive cartilage damage. Current therapeutic options are largely palliative and yet fail to achieve desired effect. In this study, we developed a combinatorial mRNA therapy using a rationally engineered lipid nanoparticle (LNP) containing a novel ionizable lipid for enhanced cartilage penetration upon intra-articular administration. This LNP co-delivers mRNAs encoding two complementary therapeutic proteins: interleukin-1 receptor antagonist (IL-1Ra) for inflammation attenuation and a C-terminal truncated derivative of angiopoietin-like 3 (ANL3) for cartilage regeneration. In pre-clinical models including collagen-induced arthritis mice, TNF-transgenic mice with spontaneous RA and destabilization of medial meniscus (DMM) surgical OA model, this "one-shot" combinatorial therapy significantly ameliorated disease severity, reduced synovitis and bone erosion, and potently promoted the regeneration of hyaline-like cartilage. Mechanistically, transcriptomic profiling of joint specimens revealed that the combinatorial therapy concurrently suppressed inflammatory pathways and extracellular matrix degradation pathways, meanwhile upregulating anabolic genes facilitating chondrogenesis. Collectively, our study establishes a versatile and synergistic mRNA therapy that offers a potent disease-modifying immunomodulatory strategy capable of addressing the long-standing unmet needs in arthritis treatment.

immunology↗

bioRxiv2025

Anti-CD206 CAR T Cell Treatment Restores Fibrosis-Induced Loss of Dermal White Adipose Tissue

Fibrosis drives pathology in the chronic autoimmune disease systemic sclerosis (SSc), which has the highest case fatality rate of any systemic autoimmune disease with no validated biomarkers or curative treatments. Our prior work has shown that CD206+ macrophages and dermal fibroblasts engage in cooperative mechanisms of inflammatory and fibrotic activation in SSc. Here, we designed a targeted immunotherapeutic approach to eliminate CD206+ macrophages using chimeric antigen receptor (CAR) T cells. We demonstrate that systemic delivery of a single dose of anti-CD206 CAR T cells restores dermal white adipose tissue (DWAT) in vivo. Notably, loss of subcutaneous fat is a well-recognized but poorly understood aspect of SSc pathogenesis that precedes the development of fibrosis and is driven by changes in lineage commitment of adipose-derived stem cells (ADSCs). Using snRNA-seq and a newly-developed in vitro co-culture model, we report that CD206high macrophages mediate ADSC shift from adipocytic to fibrotic activation in part through an IL-6-dependent mechanism. This report implicates a novel function for macrophages in the regulation of early SSc pathogenesis and is the first to establish the therapeutic efficacy of using CAR T cell immunotherapy to target macrophages in the treatment of SSc skin disease.

synthetic biology↗

bioRxiv2024

Cancer therapy via neoepitope-specific monoclonal antibody cocktails

BackgroundCellular heterogeneity presents a significant challenge to cancer treatment. Antibody therapies targeting individual tumor-associated antigens can be extremely effective but are not suited for all patients and often fail against tumors with heterogeneous expression as tumor cells with low or no antigen expression escape targeting and develop resistance. Simultaneously targeting multiple tumor-specific proteins with multiple antibodies has the potential to overcome this barrier and improve efficacy, but relatively few widely expressed cancer-specific antigens are known. In contrast, neoepitopes, which arise from mutations unique to tumor cells, are considerably more abundant. However, since neoepitopes are not commonly shared between individuals, a patient-customized approach is necessary and motivates efforts to develop an efficient means to identify suitable target mutations and isolate neoepitope-specific monoclonal antibodies. MethodsHere, focusing on the latter goal, we use directed evolution in yeast and phage display systems to engineer antibodies from non-immune, human antibody fragment libraries that are specific for neoepitopes previously reported in the B16F10 melanoma model. ResultsWe demonstrate proof-of-concept for a pipeline that supports rapid isolation and functional enhancement of multiple neoepitope peptide-targeted monoclonal antibodies and demonstrate their robust binding to B16F10 cells and potent effector functions in vitro. These antibodies were combined and evaluated in vivo for anti-cancer activity in tumor-bearing mice, where they suppressed B16F10 tumor growth and prolonged survival. ConclusionsThese findings emphasize the potential for clinical application of patient-customized antibody cocktails in the treatment of the many cancers poorly addressed by current therapies.

immunology↗

bioRxiv2019

Spatial distribution of breast cancer in Sudan 2010-2016

BackgroundBreast cancer is the most prevalent cancer among females worldwide including Sudan. The aim of this study was to determine the spatial distribution of breast cancer in Sudan.\n\nMaterials and methodsA facility based cross-sectional study was implemented in eighteen histopathology laboratories distributed in the three localities of Khartoum State on a sample of 4630 Breast Cancer cases diagnosed during the period 2010-2016. A master database was developed through Epi Info 7.1.5.2 for computerizing the data collected: the facility name, type (public or private), and its geo- location (latitude and longitude). Personal data on patients were extracted from their respective medical records (name, age, marital status, ethnic group, State, locality, administrative unit, permanent address and phone number, histopathology diagnosis). The data was summarized through SPSS to generate frequency tables for estimating prevalence and the geographical information system (ArcGIS 10.3) was used to generate the epidemiological distribution maps. ArcGIS 10.3 spatial analysis features were used to develop risk maps based on the kriging method.\n\nResultsBreast cancer prevalence was 3.9 cases per 100,000 female populations. Of the 4423 cases of breast cancer, invasive breast carcinoma of no special type (NST) was the most frequent (79.5%, 3517/4423) histopathological diagnosis. The spatial analysis indicated as high risk areas for breast cancer in Sudan the States of Nile River, Northern, Red Sea, White Nile, Northern and Southern Kordofan.\n\nConclusionsThe attempt to develop a predictive map of breast cancer in Sudan revealed three levels of risk areas (risk, intermediate and high risk areas); regardless the risk level, appropriate preventive and curative health interventions with full support from decision makers are urgently needed.

epidemiology↗