ABSTRACT
Methylmalonic acidemia (MMA) is an inborn error of metabolism mostly caused by mutations in the mitochondrial methylmalonyl-CoA mutase gene (MMUT). MMA patients suffer from frequent episodes of metabolic decompensation, which can be life threatening. To mimic both the dietary restrictions and metabolic decompensation seen in MMA patients, we developed a novel protein-controlled diet regimen in a Mmut deficient mouse model of MMA and demonstrated the therapeutic benefit of mLB-001, a nuclease-free, promoterless recombinant AAV GeneRideTM vector designed to insert the mouse Mmut into the endogenous albumin locus via homologous recombination. A single intravenous administration of mLB-001 to neonatal or adult MMA mice prevented body weight loss and mortality when challenged with a high protein diet. The edited hepatocytes expressed functional MMUT protein and expanded over time in the Mmut deficient mice, suggesting a selective growth advantage over the diseased cells. In mice with a humanized liver, treatment with a human homolog of mLB-001 resulted in site-specific genome editing and transgene expression in the transplanted human hepatocytes. Taken together, these findings support the development of hLB-001 that is currently in clinical trials in pediatric patients with severe forms of MMA.
Subject(s)
Amino Acid Metabolism, Inborn Errors , Methylmalonyl-CoA Mutase , Adult , Albumins/genetics , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/therapy , Animals , Child , Disease Models, Animal , Gene Editing , Humans , Methylmalonyl-CoA Mutase/genetics , Methylmalonyl-CoA Mutase/metabolism , MiceABSTRACT
The discovery of a small subset of cancer cells with self-renewal properties that can give rise to phenotypically diverse tumour populations has shifted our understanding of cancer biology. Targeting cancer stem cells (CSCs) is becoming a promising therapeutic strategy in various malignancies, including head and neck squamous cell carcinoma (HNSCC). Diverse sub-populations of head and neck cancer stem cells (HNCSCs) have been identified previously using CSC specific markers, the most common being CD44, Aldehyde Dehydrogenase 1 (ALDH1), and CD133, or by side population assays. Interestingly, distinct HNCSC subsets play different roles in the generation and progression of tumours. This article aims to review the evidence for a role of specific CSCs in HNSCC tumorigenesis, invasion, and metastasis, together with resistance to treatment.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinogenesis/pathology , Drug Resistance, Neoplasm , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/pathology , Neoplastic Stem Cells/pathology , Animals , Antineoplastic Agents/pharmacology , Carcinogenesis/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , Neoplasm Metastasis , Neoplastic Stem Cells/drug effectsABSTRACT
Adherence with oral hypoglycaemic agent is crucial to achieve optimal glycaemic control. The 8-item Morisky Medication Adherence Scale (MMAS-8) has been frequently used, yet the association between MMAS-8 score and glycaemic control among Chinese diabetes patients is largely unknown. Two general out-patient clinics were randomly selected in a district with socio-demographic characteristics representative of the entire Hong Kong population. A consecutive sample of adult type-2 diabetes patients currently taking oral hypoglycaemic agents was included. The glycaemic control was reflected by the level of hemoglobin A1c (HbA1c) taken within the previous 6 months. Factors associated with poor glycaemic control (HbA1c ≥ 7.0%) were evaluated by linear regression analysis. From 565 eligible Chinese patients with an average age of 63.2 years (SD 9.7) and male proportion of 46.5%, the average HbA1c was 7.1% (SD 1.1%), and 52.0% had poor glycaemic control. The proportion of poor medication adherence (MMAS-8 ≤ 6) was 32.2%. After controlling for socio-demographics, lifestyle, medication use, and health characteristics, the MMAS-8 score was correlated with better glycaemic control (beta -0.095; 95%CI -0.164 to -0.026, P = .007). The MMAS-8 score had a weak and negative correlation with HbA1c level. The instrument should be applied with caution when predicting glycaemic control in clinical practice.
