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Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
Correctors improve CFTR folding either by direct binding or by adapting protein homeostasis (Mijnders, Kleizen, and Braakman, 2017). This modulator corrects the misfolded CFTR protein, thereby restoring it to its original three-dimensional form. Thus, it accelerates the functioning of the CFTR protein through its movement toward the cell surface (Almughem et al., 2020). These also increase gating and conductance. The first two correctors identified by high-throughput screening of a small-molecule library were bis-aminomethylbithiazole C4 (Corr-4a) and quinazolinole C3 (VRT-325) (Mijnders, Kleizen, and Braakman, 2017). VX-809 (Lumacaftor) is the first corrector to undergo extensive trials (Shanthikumar and Massie, 2017). It is used to correct the F508del mutation, the most common type of CF mutation. This helps avoid the ER-mediated degradation of the CFTR macromolecule by enhancing the interaction between the NBD1, MSD1, and MSD2 domains (Almughem et al., 2020). VX-661 is considered to be an improved VX-809 analog. The correctors, VX-440, VX-152, and VX-659, are also studied in clinical trials (Mijnders, Kleizen, and Braakman, 2017). Correctors GLPG2222 and GLPG2851 (C1) are additive to GLPG2737 and GLPG3221 (C2) and may be combined in therapy. GLPG2222 have structural similarities with VX-809 and VX-661 but is known to be more potent. Combinations of C1, C2, and a potentiator developed by Galapagos/ AbbVie significantly increase chloride transport over Orkambi (VX-809 and VX-770) in vitro (Mijnders, Kleizen, and Braakman, 2017). Corrector modulators are usually used in combination with potentiator modulators in CF treatment. Examples are the FDA-approved Orkambi® (lumacaftor combined with ivacaftor) and Symdeko™ (tezacaftor combined with ivacaftor) (Almughem et al., 2020). The tezacaftor/ivacaftor combination has been shown to have fewer side effects, such as chest tightness and drug interactions, than lumacaftor/ivacaftor (Cystic Fibrosis Foundation ) Tezacaftor, in combination with Lumacaftor and Ivacaftor, have shown a promising moderate improvement (Fiore et al., 2019). On October 21 2019, the US Food and Drug Administration approved a new triple-combination therapy (elexacaftor/tezacaftor/ivacaftor), including two correctors and one potentiator combination, for individuals with CF who are aged 12 years and older and have at least one allele with the F508del mutation (2019 PATIENT REGISTRY ANNUAL DATA REPORT, 2021). The efficacy of Trikafta in patients with cystic fibrosis aged 12 years and older was manifested in two trials. The first trial consisted of a 24-weeks randomized, double-blind, placebo-controlled trial done on 403 patients who had an F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein which is not responsive to ivacaftor or tezacaftor/ivacaftor alone. The second trial was a 4-weeks randomized, double-blind, active-controlled trial with 107 patients who had two identical F508del mutations (U.S. Food & Drug Administration, 2019)
Perceptions of airway gene therapy for cystic fibrosis
Published in Expert Opinion on Biological Therapy, 2023
Martin Donnelley, David Parsons, Ivanka Prichard
Given the advances in technology and the recent emergence of effective CFTR modulator therapies, it is important to establish the current perceptions that parents hold toward gene therapy for children with CF. In addition, research is yet to examine the perceptions of CF patients themselves toward gene therapy. This understanding is of critical importance, as parents’ and patients’ beliefs about the efficacy and safety of a therapy will influence their willingness to participate in clinical trials [17,18]. The aim of this project was therefore to examine the perceptions toward gene therapy for CF among people with CF, their families, and people who knew someone with CF. This was done over two cross-sectional quantitative survey studies. The first of these (Study 1) was conducted in 2017, prior to the availability of a CFTR modulator therapy for people homozygous for the Phe508del mutation. When the highly effective modulator therapy Trikafta became widely available in the USA (but was not available in Australia) we decided to perform a second study (Study 2) in 2020, to assess whether perceptions had changed once a highly effective pharmaceutical treatment was available for some patients.
Adolescent and caregiver mental health, pulmonary function, and healthcare utilization in pediatric cystic fibrosis
Published in Children's Health Care, 2022
Areti Vassilopoulos, Melissa Swartz, Shruti Paranjape, Keith J. Slifer
Cystic fibrosis (CF) is the most common life-limiting, inherited pediatric chronic disease in the United States, exceeding 13,000 children under 18-years-old (Cystic Fibrosis Foundation, 2019). CF is an autosomal recessive disorder resulting from a genetic mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. According to the newest project within the Cystic Fibrosis Mutation Database, the Clinical and Functional Translation of CFTR (CFTR2), as of July 2020 in a database of 89,052 patients, 442 disease-causing variants were annotated, 360 of which were CF-causing (CFTR2, http://cfrt.org). Malfunction or deficiencies of the CFTR gene cause abnormal coagulation of thick mucus secretions that lead to multi-systemic disease and organ failure. Complications of CF, such as persistent pulmonary inflammation and bacterial infection, exocrine pancreatic insufficiency, and cystic fibrosis-related diabetes (CFRD) are associated with increased morbidity and mortality (Lobo & Noone, 2014). However, advancements in the treatment of CF have enhanced life expectancy from 10-years-old in 1962 to the current median predicted survival age of 47-years-old (Cystic Fibrosis Foundation, 2019). Revolutionizing CF treatment, innovative CFTR modulator therapies are the most recent medical advancements. In October 2019, the United States Federal Drug Administration (FDA) approved Trikafta ™, a triple molecular combination therapy for treatment of the most common CFTR mutation, F508del (Ridley & Condren, 2020).
Are academia–pharma partnerships essential for novel drug discovery in the time of the COVID-19 pandemic?
Published in Expert Opinion on Drug Discovery, 2021
Even when the research efforts of pharmaceutical companies lead to significant therapeutic benefits, these are usually accompanied by significant financial rewards. For example, between 2013 and 2018 revenue to Gilead from sales of its hepatitis C drugs is estimated to have been 58.6 USD billion of which 25.8 USD billion was profit[13]. Vertex, the maker of Trikafta (elexacaftor/tezacaftor/ivacaftor and ivacaftor) the new treatment for cystic fibrosis, earned 420 USD million in the first 10 weeks that the drug was on the market in the US[14]. In fairness, it also needs to be acknowledged that skewed research priorities are not exclusive to industry. Moradpour and Hollis show that when research is sponsored by non-industry-funded sources (governments, universities, and foundations) that there is still a bias in favor of diseases that affect wealthy populations[15].