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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Lonafarnib is orally bioavailable and has been shown in preclinical studies to inhibit farnesyltransferase, although the precise mechanism has not been established. For example, some studies have suggested that it may also act through non-Ras mediated mechanisms. For example, in progeria (see below), the mechanism appears to involve inhibition of prenylation of the progerin protein (i.e., mutant prelamin A), which carries the same CAAX carboxy-terminal motif as the Ras proteins.
Telomeres and Cardiovascular Diseases
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Vicente Andrés, Beatriz Dorado, Ioakim Spyridopoulos
Premature aging disorders, such as HGPS or Werner syndrome, are characterized by precocious CVD and a severely reduced life span (Trigueros-Motos et al. 2011). Mechanisms thought to contribute to the etiopathogenesis of both diseases include transcriptional alterations, impaired DNA repair, accelerated telomere attrition and premature cellular senescence (Andrés and González 2009). In HGPS, mutations in the LMNA gene (encoding A-type lamins) lead to abnormal accumulation of progerin, which unlike mature wild-type lamin A remains permanently farnesylated. This accumulation disrupts the nuclear lamina and leads to a multitude of nuclear defects. Interestingly, in normal cells progressive telomere damage during cellular senescence activates progerin production, a mechanism through which low progerin expression might contribute to normal aging (Cao et al. 2011).
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Causative genes in DCM predominantly encode two major subgroups of proteins – cytoskeletal and sarcomeric proteins. The cytoskeletal proteins identified so far include dystrophin, desmin, lamin A/C, δ-sarcoglycan, β-sarcoglycan and metavinculin. The TTN gene encodes the giant protein titin, which is the largest known protein expressed in the heart and functions as a spring, providing passive force and regulating sarcomere contraction and signalling. It spans half the length of the sarcomere from Z disc to M band and is referred to as a third filament with the thin and thick filaments of the sarcomere. It is now established that truncating variants of TTN contribute to 20–25% of DCM. In the case of sarcomere-encoding genes, the same genes identified for HCM appear responsible, including actin (ACTC), β-myosin heavy chain (MYH7), troponin T (TNNT2), α-tropomyosin (TPM1) and cardiac myosin binding protein C (MYBPC3), as well as Z-disc proteins such as muscle LIM protein, cypher/ZASP, and titin (TTN). Mutations in the gene encoding lamin A/C, a component of the nuclear envelope, are an important cause of familial DCM. LMNA missense and truncating mutations account for 5–8% of genetic DCM. The single LMNA gene encodes lamins A and C, and differential splicing at the 3′ end results in 2 proteins that are identical across their first 566 amino acids; mutations in LMNA lead to a constellation of diseases from premature ageing to myopathies and DCM. Mutations that alter processing of lamin A lead to accumulation of prelamin A (sometimes called progerin), and these have been associated with the premature ageing syndrome Hutchinson–Gilford progeria. LMNA mutations associate frequently with dysrhythmias that includes sinus node dysfunction, atrial fibrillation, atrioventricular node dysfunction, ventricular fibrillation and SCD. Cardiac conduction system disease may precede the development of LV dilation and dysfunction, and the presence of early conduction system disease may suggest LMNA mutation. The PLN gene encodes phospholamban, a 52 amino acid residue transmembrane protein that, when unphosphorylated, inhibits sarcoplasmic reticulum Ca2+-ATPase. Several dominant mutations in PLN have been associated with DCM, including the R14del mutation that is a founder mutation in the Netherlands and Germany. Thus, in some populations, the percentage of DCM due to PLN mutations is high. The phenotype with PLN mutations is variable. Early onset DCM with lethal ventricular arrhythmias is described but also cases that look like arrhythmogenic cardiomyopathy. Individuals from the Netherlands with the R14del founder mutation have a severe phenotype. Identifying the same primary mutation(s) with a range of phenotypes supports the concept that other factors modify the outcome of PLN-mediated DCM. mRBM20, RNA-binding motif 20 is an RNA-binding protein expressed highly in both atria and ventricle. Dominant mutations in the RBM20 gene contribute to 1–5% of DCM.
Pluripotent stem cells for neurodegenerative disease modeling: an expert view on their value to drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Shi-Dong Chen, Hong-Qi Li, Mei Cui, Qiang Dong, Jin-Tai Yu
Extending the culture period of iPSC-derived neural cells has been introduced to tackle this problem. Cells are considered more matured by prolonged cultivation. Besides, the direct differentiation of somatic cells to the neural cell of the target has also been developed, by which the original aging signature could not be eliminated by the reprogramming procedure. However, both approaches erode the strength of iPSC in disease modeling. While the extension of culturing increases time costs, the neurons that are directly differentiated are postmitotic cells that cannot expand the way iPSCs do. These drawbacks can greatly impact the efficiency of drug discovery. A deeper understanding of how epigenetic factors take effect in disease pathophysiology is fundamental, which could guide the exploration of the usage of epigenetic regulation during age-related disease modeling. At present, the overexpression of external compounds like progerin to accelerate the cellular maturation process is promising [118]. Manipulation of telomerase is an alternative way worth trying [118]. More efforts are needed in future researches to clearly identify the molecular mechanism of cell aging.
Progress in understanding Friedreich’s ataxia using human induced pluripotent stem cells
Published in Expert Opinion on Orphan Drugs, 2019
Anna M. Schreiber, Julia O. Misiorek, Jill S. Napierala, Marek Napierala
The first symptoms of FRDA typically present between the ages of 5–15 years, however patient cells have had to cope with a reduced level of frataxin since embryogenesis [52,53]. Although clinical presentation of symptoms is presumably preceded by pathological changes at the molecular and cellular levels, the timeline of FRDA manifestation is certainly longer than a few weeks of differentiation of iPSC lines into neuronal or cardiac cells. Therefore, identifying robust phenotypes in relatively young and immature cells may be difficult if not impossible. Perhaps accelerating the aging process by exogenous expression of progerin as demonstrated in Parkinson’s disease iPSC studies [82] would result in early manifestation of some of the more severe, typically late-onset anomalies detected in FRDA. Another potential solution could be a transdifferentiation approach whereby one type of somatic cell (e.g. fibroblasts) are directly converted into another type of somatic cell (e.g. induced neurons, iNs) using specific growth factors and expression of lineage-specific transcription factors. This method would bypass possible ‘rejuvenation’ introduced at the pluripotent cell stage [83–85].
Progeria: a perspective on potential drug targets and treatment strategies
Published in Expert Opinion on Therapeutic Targets, 2022
Ignacio Benedicto, Xue Chen, Martin O Bergo, Vicente Andrés
Progerin exerts a dominant-negative effect, inducing multiple cellular and organismal alterations. HGPS patients appear normal at birth, and the first disease symptoms are growth failure and alopecia, typically appearing in the first or second year of life. Over time, additional symptoms develop and worsen, including dermal and bone abnormalities, joint contractures, and lipodystrophy. Although patients typically lack most traditional cardiovascular risk factors, their main medical problem is severe cardiovascular disease, including generalized atherosclerosis and vascular calcification and stiffness, which can ultimately provoke fatal myocardial infarction, stroke, or heart failure [3].