Search

Most rare diseases (RDs) encompass a diverse group of inherited disorders that affect millions of people worldwide. A significant proportion of these diseases are driven by functional haploinsufficiency, which is caused by pathogenic genetic variants. Currently, most treatments for RDs are limited to symptom management, emphasizing the need for therapies that directly address genetic deficiencies. Recent advancements in gene therapy, particularly with adeno-associated viruses (AAVs) and lipid nanoparticle-encapsulated messenger RNA (mRNA), have introduced promising therapeutic approaches. AAV vectors offer durable gene expression, extensive tissue tropism, and a safety profile that makes them a leading choice for gene delivery; however, limitations remain, including packaging size and immune response. In contrast, mRNA therapeutics, formulated in LNPs, facilitate transient protein expression without the risk of genomic integration, supporting repeated dosing and pharmacokinetic control, though with less long-term expression than AAVs. This review analyzes the latest developments in AAV and mRNA technologies for rare monogenic disorders, focusing on preclinical and clinical outcomes, vector design, and delivery challenges. We also address key regulatory and immunological considerations impacting therapeutic success. Together, these advancements in AAV and mRNA technology underscore a new era in RD treatment, providing innovative tools to target the genetic root of these diseases and expanding therapeutic approaches for patients who currently face limited medical options. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) is associated with progressive changes contributing to clinical complications related to macro- and microvascular diseases. Garlic (Allium sativum L.) and its organosulfur components have been related to beneficial cardiovascular effects and could improve endothelial function. The ENDOTALLIUM Study aimed to evaluate the effect of the regular consumption of encapsulated purple garlic oil on microvascular function, endothelial-related biomarkers, and the components of metabolic syndrome (MetS) in untreated subjects with cardiometabolic alterations. Fifty-two individuals with at least one MetS component were randomized (1:1) in a single-center, single-blind, placebo-controlled, parallel-group study. The participants received encapsulated purple garlic oil (n = 27) or placebo (n = 25) for five weeks. Skin microvascular peak flow during post-occlusive reactive hyperemia significantly increased in the purple garlic oil group compared to the placebo group (between-group difference [95%CI]: 15.4 [1.5 to 29.4] PU; p = 0.031). Likewise, hs-CRP levels decreased in the purple garlic group compared to the control group (−1.3 [−2.5 to −0.0] mg/L; p = 0.049). Furthermore, we observed a significant reduction in the mean number of MetS components in the purple garlic group after five weeks (1.7 ± 0.9 vs. 1.3 ± 1.1, p = 0.021). In summary, regular consumption of encapsulated purple garlic oil significantly improved microvascular function, subclinical inflammatory status, and the overall MetS profile in a population with cardiometabolic alterations. [ABSTRACT FROM AUTHOR]

Hereditary hemorrhagic telangiectasia is an inherited disease related to an alteration in angiogenesis, manifesting as cutaneous telangiectasias and epistaxis. As complications, it presents vascular malformations in organs such as the lung, liver, digestive tract, and brain. Currently, diagnosis can be made using the Curaçao criteria or by identifying the affected gene. In recent years, there has been an advance in the understanding of the pathophysiology of the disease, which has allowed the use of new therapeutic strategies to improve the quality of life of patients. This article reviews some of the main and most current evidence on the pathophysiology, clinical manifestations, diagnostic approach, screening for complications, and therapeutic options, both pharmacological and surgical. [ABSTRACT FROM AUTHOR]

Elevated C-reactive protein (CRP) levels it has behaved as a marker of the insulin resistance (IR) syndrome, DM and endothelial dysfunction (ED). But what is happening backstage at the vascular bed of these individuals which makes them so vulnerable? ALMS: l-To determine the prevalence of the elevated high sensitivity CRP in a cardiovascular risk policlinic. 2-To correlate hsCRP levels with ambulatory blood pressure monitoring, elasticity and endothelium and non-endothelium dependent vasodilation. METHODS: N= 113, aged 59,81 +- 1,36, m/f: 56/57;77 with hypertension. BMI.Waist (cm). W/H ratio, hsCRP (mR/L): DRG EIA. Insulin-resistance (IR)(HOMA) Insulin-sensitivity (IS)(QUICKY score) Ambulatory blood pressure monitoring (ABPM). SBP, DBP, MAP; ambulatory pulse pressure (APP). Endothelium and non-endothelium dependent vasodilation (EDV and NEDV) in the macrocirculation (Celermajer method) and in the microcirculation (laser Doppler-Moor, DRT4). Large (C1) and small (C2) artery elasticity indexes (HDI/CR-2000). Statistical: Kruskal-Wallis, Bonferroni, Dunnett, ANOVA, Pearson, Multivariate L. Regression. RESULTS: 1-Groups according to hsCRP levels: A(<1 mg/L): N=31; B (1-3 mg/L): N=23; C (>3 mg/L): N=59. Groups A and B, as well as B and C, are comparable by age. There was a correlation between IR/IS and hsCRP, which was not present when matched by age. 2-In ABPM: Statistically significant difference between B and C for SBP (p=0,017), and for APP (p= 0,049). Positive linear correlation between hsCRP and APP (p=0,001), which was not statistically significant when matched by age. 3-There were differences in C1 and C2: C1 at the borderline of statistical significance between groups A and C (p=0,05). C2: with a statistically significant difference A/C (p=0,002) and B/C (p=0,027). 4- Statistically significant differences between groups B and C for the macro-NEDV (p=0,020). 5-We found a negative linear correlation between hsCRP and NEDV (p=0,003), being age a probable correction factor for this relation. 6- There was a statistically significant difference in the peak-flow of the skin between groups A and C (p=0,038). CONCLUSIONS: 1- The prevalence of borderline levels of hsCRP is 20,4%, and 52,2% for high levels of hsCRP. 2-hsCRP correlates with micromacrovascular elasticity. 3-hsCRP correlates with micro-EDV and with macro-NEDV. 4-Now we do know what happens backstage when having elevated hsCRP levels. ADA-Funded Research [ABSTRACT FROM AUTHOR]

Total vascular impedance (TVI) characterizes the impediment presented by the arterial tree to the setting-up of the blood flow and pressure. Information provided by TVI could be of fundamental interest to haemodynamic studies or even as an instrument for clinical diagnosis. AIMS: 1-To evaluate the association of clinical and metabolic parameters with TVI. 2-To compare TVI between hyperglycaemic and normoglycaemic groups. METHODS: N=101, 22-89 years. 54/47 M/F ratio. 52, 5% DM2, 71,3% hypertensives, 25% smokers. BMI (kg/m2) and W(cm). Creat, gly, TG, LDL, HDL, total-Chol by HITACHI. Hyperglycaemia according to: American Diabetes Association. Glomerular Filtration Rate(GFR):Cokroft-Gault Equation. Endothelium and non-endothelium dependent (EDV;NEDV): Celermajer Extracellular matrix activity: COMP(U/L): ELISA.hs-CRP(mg/I):ELISA. Ambulatory Blood Pressure Monitoring: Spacelabs 90207.24-hour average systolic, diastolic and mean blood pressure (aSBP, aDBP, aMBP).HbA1c(%):HPLC. Total vascular impedance (dyne.sec.cm5): HDI/ PulseWave CR-2000. Statistical analysis: Mann-Whitney, Chi-squared and Student's T tests. Pearson's coefficient correlation. Multivariate linear regression. RESULTS: 1. TVI presented high correlation with age(p<0,001), with a linear regression slope of β=3,255(p<0,001). 2. Based on experimental data, the cut-off point for increased TVI was set at the 75 percentile. Comparing both groups, normal(TVI<230; n=76) vs increased(TVI≥230; n=25), statistically significant differences were found in age(p<0,001), percentage of fat mass(p=0,001), GFR(p=0,048), NEDV(p=0,012), aDBP(p=0,001), COMP (p=0,042) and hs-CRP (p=0,020). Multivariate linear regression analysis showed that NEDV(p=0,047), and aDBP(p=0,010) were directly related to TVI, adjusting by age and percentage of fat mass. 3. Comparing prediabetic-diabetic patients (n=40) vs non-diabetic patients (n=40), with similar age no significant differences were found in TVI. CONCLUSIONS: 1. Age is the most important factor implicated in TVI, measured by a cardiovascular profiling system. 2. aDBP and NEDV, but not GFR, COMP nor CRP, are directly related to TVI. 3. Unlike NEDV, EDV is not influenced by TVI. 4. Diabetic status, at similar age, does not influence TVI. ADA-Funded Research [ABSTRACT FROM AUTHOR]