INDREPTA C: A new Indrepta designed to promote lung health
Recently it was announced that Ataluren, a drug designed to treat cystic fibrosis nonsense mutations, has failed to demonstrate improved lung function in CF patients in phase III clinical trials.1 This blow for the CF community is substantially softened by a recent publication demonstrating that already clinically available therapies, including “a readily available herbal agent with no known side effects” (escin), may be effective in suppressing CFTR nonsense mutations. 2 This is welcome news to approximately 15% of CF patients who carry one or more of over 150 CFTR nonsense mutations known to cause disease through creation of a premature stop codon. Suppressing nonsense mutations through the action of a supplement or drug capable of promoting read-through to produce full length functional CFTR is a therapeutic goal. A complete list of CFTR nonsense mutations can be found at the Hospital for Sick Children in Toronto’s CFTR Mutation Database .3 We provide a table of CFTR nonsense mutations derived from this resource below.
Escin is a pentacyclic triterpene isolated from the flowering tree Aesculus hippocastanum, commonly known as horse chestnut. Used safely for many years to treat inflammatory and vascular conditions, Escin is available in many countries under a variety of brand names. 4 Because it is commonly observed that combinations of compounds are more effective than single therapies for improving CFTR function; an observation borne out with escin in combination with a potentiator,2 we sought to discover other potential suppressors of nonsense mutations through a structural similarity search based on Escin. This search produced the pentacyclic triterpene Boswellic acids that are found in the resin of the plant Boswellia serrata. Like escin, Boswellic acids are also widely used herbal therapies that are GRAS (Generally Recognized As Safe by the US Food and Drug Administration). Also known as frankincense, Boswellia is an especially ancient therapy used to treat pain and inflammation. Interestingly, Ali and Mansour reported in 2011 that oral administration of Boswellic acids attenuates pulmonary fibrosis in a mouse model of this disease; notably for CF, in part through suppression of neutrophil migration, suppression of the pro-inflammatory mediator TGF-, and through inhibition of 5-Lipoxygenase (5-LOX), preventing lung injury. 5
We combined escin and Boswellic acids in a formulation with other GRAS herbal ingredients to create a new supplement called Indrepta C. Indrepta C is based on Indrepta B because recovery of residual function through suppression of CFTR nonsense mutations is demonstrated to be possible with escin2 and may be further improved by Boswellic acids. Curcumin, an ingredient in all Indreptas, is shown to improve function of the common nonsense mutation W1282X. 6 Therefore any residual function gained from the nonsense mutations would theoretically benefit from Indrepta B’s forskolin, which increases CFTR-activating cyclic AMP, and also amentoflavone, a biflavonoid that is a phosphodiesterase inhibitor which helps to maintain activity of cyclic AMP. Forskolin is an old asthma remedy, 7 which may exert its beneficial effects in asthmatics at least in part through CFTR.
The Indrepta formulations A, B and now C represent our best current knowledge of anti-inflammatory and CFTR-active ingredients likely to be beneficial to patients with cystic fibrosis. All ingredients used in the Indreptas are GRAS. GRAS status means that these natural food and herb-derived compounds are well studied in humans (most have clinical trials you can find online) and are known to be safe. It is always possible, however, that some individuals may have or could develop allergies to any food or herb. CF patients with very low lung function are fragile and may be especially vulnerable to detox reactions or any change for that matter in their lung environment. We recommend that any new supplement regimen is started slowly, increasing very gradually to a full dose that best suits each individual.
Cystic fibrosis remains a fatal disease, with no effective disease modifying treatment available for most patients. Currently, patients with nonsense mutations have no available therapy. Therefore we have a sense of urgency to provide to patients any GRAS ingredient with good evidence of potential benefit in CF as quickly as possible, and in a form that is likely to be bioavailable. We use only standardized extracts and test each batch to ensure consistency, quality and safety.
All Indreptas are composed of multiple ingredients known to fight inflammation in humans. Reduction in inflammation is associated with improved lung function even in normal individuals. Patients on statins, which are known to be anti-inflammatory, show less age related lung function decline than age matched controls not taking statins. 8 Subsequently it was shown that use of statins among lung transplant patients is associated with better graft survival and function. 9
In addition to anti-inflammatory benefits, Indreptas A-C are formulated with ingredients demonstrated to be CFTR-active. Thus far, new pharmaceutical CFTR-active drugs have worked well for only a small percentage of CF mutations, and clinical trials to develop treatments for less common CF mutations are not cost effective for pharmaceutical companies. But, by working together, we can develop and test natural therapies right now for patients in the U.S. and worldwide. Your participation and feedback makes all the difference.
1. Joana Fernandez. March 6, 2017. Ataluren Fails to Pass Muster as Treatment for Severe Form of Cystic Fibrosis. Article in Cystic Fibrosis News Today. https://cysticfibrosisnewstoday.com/news/2017/03/06/ataluren-fizzles-in-clinical-trial-against-severe-form-of-cystic-fibrosis/ .
2. Mutyam V, Du M, Xue X, Keeling KM, White EL, Bostwick JR, Rasmussen L, Liu B, Mazur M, Hong JS, Falk Libby E, Liang F, Shang H, Mense M, Suto MJ, Bedwell DM,Rowe SM. Discovery of Clinically Approved Agents That Promote Suppression of Cystic Fibrosis Transmembrane Conductance Regulator Nonsense Mutations. Am J Respir Crit Care Med. 2016 Nov 1;194 (9):1092-1103. PubMed PMID: 27104944; PubMed Central PMCID: PMC5114449.
3. Cystic Fibrosis Mutation Database; http://www.genet.sickkids.on.ca/Home.html accessed 3/11/2017.
4. Drugs.com; https://www.drugs.com/international/escin.html accessed 3/11/2017.
5. Ali EN, Mansour SZ. Boswellic acids extract attenuates pulmonary fibrosis induced by bleomycin and oxidative stress from gamma irradiation in rats. Chin Med. 2011 Sep 30;6:36. doi: 10.1186/1749-8546-6-36. PubMed PMID: 21961991; PubMedCentral PMCID: PMC3199276.
6. Wang W, Hong JS, Rab A, Sorscher EJ, Kirk KL. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators. PLoS One. 2016 Mar 23;11(3):e0152232. doi:10.1371/journal.pone.0152232. PubMed PMID: 27007499; PubMed Central PMCID: PMC4805204.
7. González-Sánchez R, Trujillo X, Trujillo-Hernández B, Vásquez C, Huerta M, Elizalde A. Forskolin versus sodium cromoglycate for prevention of asthma attacks: a single-blinded clinical trial. J Int Med Res. 2006 Mar-Apr;34(2):200-7. PubMed PMID: 16749416.
8. Alexeeff SE, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J. Statin use reduces decline in lung function: VA Normative Aging Study. Am J Respir Crit Care Med. 2007 Oct 15;176(8):742-7. PubMed PMID: 17673694; PubMed Central PMCID:PMC2020828.
9. Li Y, Gottlieb J, Ma D, Kuehn C, Strueber M, Welte T, Simon AR, Warnecke G, Haverich A. Graft-protective effects of the HMG-CoA reductase inhibitor pravastatin after lung transplantation–a propensity score analysis with 23 years of follow-up. Transplantation. 2011 Aug 27;92(4):486-92. doi:10.1097/TP.0b013e318225670d. PubMed PMID: 21712756.