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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The agent has been investigated in clinical trials for the treatment of progeria, a rare genetic disorder in which symptoms of aging occur prematurely. A Phase II clinical trial was completed in 2012, which demonstrated that a combination of lonafarnib and two other agents met clinical efficacy endpoints. In another clinical study in patients with metastatic NSCLC who had failed previous taxane regimens, lonafarnib was found to have some antitumor activity in the 29 patients studied, with 3 achieving partial responses, an overall 16-week average disease-free progression survival time and an average overall survival of 39 weeks. However, these results were insufficient for further progression of lonafarnib. Minimal side effects were observed with this combination of paclitaxel and lonafarnib, with fatigue, diarrhea, and dyspnea being the most frequent side effects. Only one patient had a significant reduction in white blood cell count and reports of more serious side effects such as respiratory insufficiency and acute respiratory failure were infrequent.
The Injured Cell
Published in Jeremy R. Jass, Understanding Pathology, 2020
Ageing has been studied at the level of the cell, and studies have shown that normal fibroblasts have a limited lifespan in culture. Fibroblasts from subjects with a rare disorder called progeria who suffer from premature ageing have a reduced lifespan under the same cell culture conditions. By contrast, malignant cells may be immortalised.
How fast do we change?
Published in Patrick Rabbitt, The Aging Mind, 2019
It is a very different question whether, and to what extent, our genetic inheritance determines our lifespans and so also affects how long we can keep our mental abilities in old age. Unfortunate children who are born with progeria, a genetically heritable condition, begin to show all the familiar signs of biological aging, including loss of brain tissue and consequent declines in mental ability in their teens, and live very short lives [21]. This extremely rare condition is not evidence that the rates at which the rest of us age are absolutely determined by our genes. It is quite possible that there may also be “long-life” genes that increase the odds of living to a greater and an intellectually more vibrant age. It has been very hard to test this because any inherited biological advantage such as a better immune system will lead to healthy and longer life and so will help to preserve the integrity of our brains and allow us to keep our wits for longer.
Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Initially designed as a cancer therapeutic, the use of lonafarnib as an HDV therapeutic is predicated upon the inhibition of prenylation of L-HDAg. Distinct from entry inhibition, prenylation in HDV is necessary for HDV viral assembly. Boosting of lonafarnib with ritonavir has allowed for increase in serum drug levels while minimizing adverse gastrointestinal side effects without evidence of viral resistance. Triple therapy with lonafarnib, ritonavir, and pegylated interferon has resulted in a significant reduction in HDV RNA and is currently in phase 3 investigation. Notably, lonafarnib has received orphan drug designation by the U.S. FDA and EMA along with fast track and breakthrough designation by the U.S. FDA and PRIME designation by the EMA for HDV and has been approved for use by the FDA for the treatment of Hutchinson-Guilford Progeria Syndrome and processing-deficient progeroid laminopathies. Lonafarnib is taken orally, which may facilitate daily administration and patient adherence.
Degree of arterial stiffness is comparable across inflammatory joint disease entities
Published in Scandinavian Journal of Rheumatology, 2022
FK Föhse, S Rollefstad, E Ikdahl, G Wibetoe, J Sexton, J Hisdal, AG Semb
Increased arterial stiffness was not associated with longer disease duration or elevated IJD disease activity markers (C-reactive protein and erythrocyte sedimentation rate). This is in agreement with previous studies but in contrast to others, as has been pointed out in a meta-analysis by Weng et al (49). It appears that increased arterial stiffness results primarily from the thickening and reduced elasticity of large conduit arteries over time, rather than the cumulative burden of inflammation. This concurs well with a study demonstrating accelerated vascular stiffening in children with progeria syndrome, who are ageing prematurely (50). Low inflammation parameters in patients with high aPWV that do not differ from patients with low aPWV may also result from more aggressive anti-inflammatory therapy.
Failure of immunosurveillance accelerates aging
Published in OncoImmunology, 2019
Maria Perez-Lanzon, Laurence Zitvogel, Guido Kroemer
A recent paper by Ovadya et al.9 now provides strong evidence for a direct link between failing immunosurveillance and accelerated aging. The authors show that perforin-1 deficient mice (genotype: Prf1−/-), which lack functional cytotoxic (T, NK or NKT) lymphocytes accumulate more senescent cells (phenotype: positive for senescence-associated-β-galactosidase, p16/Cdkn2a, p15/Cdkn2b, p53, p53BP1 foci, γH2AX foci, nuclear p65/RelA subunit of NF-κb, DcR2; negative for HMGB1) in multiple organs (such as bronchial epithelia, liver, pancreas and skin epidermis) along with signs of inflammation with overexpression of SASP components as well as increased infiltration of organs by T, NK and NKT cells, leukocytosis and splenomegaly. In addition, Prf1−/- mice exhibited multiple signs of premature and aggravated aging with increased fibrosis of kidney, liver, pancreas, and skin, glomerular sclerosis, loss of subcutaneous adiposity, reduced hair density, increased prevalence of gray hair, reduced muscle strength, exaggerated kyphosis, and a reduced median lifespan. Importantly, this phenotype was attenuated by treating mice with the senolytic agent ABT-737, which reduced the accumulation of senescent cells and decreased histological, functional and transcriptional signs of aging.9 Moreover, in a mouse model of Hutchinson–Gilford progeria syndrome (HGPS) with the LMNA+/G609G genotype, knockout of Prf1 accelerated the premature aging phenotype and this effect could again be alleviated by administration of ABT-737.9