Since 1989 when the gene responsible for cystic fibrosis was cloned and designated the cystic fibrosis transmembrane conductance regulator cftr gene, considerable progress has been made in the development of gene therapy for this disease. Cystic fibrosis transmembrane regulator replacement therapy cystic fibrosis transmembrane regulator pharmacotherapy stimulation of alternative chloride channels inhibition of sodium absorption airway rehydration summary since the detection of the underlying gene defect, our knowledge of how the genetic mutations in. Despite advances in nutritional management, aggressive antibiotic usage, and physiotherapy, cystic fibrosis cf remains a life limiting illness with high morbidity that imposes considerable burdens on children and families. Prospects for gene therapy in cystic fibrosis archives of. The cftr gene was first discovered in 1989, and different mutations in the cftr gene result in functional changes to the cftr protein, grouped into 6 distinct classes 3 figure 1. For this reason, scientists are exploring ways to provide a correct copy of the gene to treat cf. Alton department of gene therapy, imperial college london, london, united kingdom the report of the. We funded the uk gene therapy consortium gtc to develop a gene therapy product with the potential to correct the faulty cystic fibrosis gene in the lungs. Advances in cell and genebased therapies for cystic. The cystic fibrosis trust has more information on genetic testing for cystic fibrosis pdf, kb. Cystic fibrosis cf is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene that. May 29, 2012 gene therapy is being developed as a novel treatment for cystic fibrosis cf, a condition that has hitherto been widelyresearched yet for which no treatment exists that halts the progression of lung disease. Talenmediated gene targeting for cystic fibrosis gene therapy. Essay on cystic fibrosis and gene therapy 2215 words.
Although cf is a multiorgan system disease, most people with. Gene therapy for the treatment of cystic fibrosis tacg. Cftr normally acts as a cyclic adenosine monophosphate. In vivo gene transfers have been accomplished in cf patients. Gene therapy is being developed as a novel treatment for cystic fibrosis cf, a condition that has hitherto been widelyresearched yet for which no treatment exists that halts the progression of lung disease. Gene therapy as a potential cure for cystic fibrosis. Nov 27, 2018 cystic fibrosis cf is a progressive, chronic and debilitating genetic disease caused by mutations in the cf transmembraneconductance regulator cftr gene. Gene therapy efforts have focused on treating the lung, since it manifests the. It is a promising approach to treat diseases, where conventional drug treatments fail. Triple combination therapy for cystic fibrosis is here. Below is a timeline showing how fast genetic research can sometimes lead to new attempts to treat a disease. The gtc announced results from the phase 2b clinical trials of its wave 1 gene therapy product in 2015. Advances in cell and genebased therapies for cystic fibrosis. Third, cystic fibrosis mouse survival is also influenced by genetic background because there are modifier genes that reduce gastrointestinal.
Cystic fibrosis cf is a chronic autosomic recessive syndrome, caused by mutations in the cf transmembrane conductance regulator cftr gene, a. Cystic fibrosis gene therapy in the uk and elsewhere. Gene therapy involves the transfer of correct copies of cystic fibrosis transmembrane conductance regulator cftr dna to the epithelial cells in. Cystic fibrosis cf occurs when both alleles of the cftr gene contain a mutation which blocks the trafficking andor function of the cftr protein, andor affects the integrity or stability of its mrna. Unfortunately, larsons report does not tell us the percentage of the cftr and lacz treated mice that survived. It is important to note that the cargoes for gene therapy and gene editing likely will differ. Gene therapy for the treatment of cystic fibrosis imperial spiral. To date, more than 20 clinical trials have been conducted with a variety of. Laube, phd theoretically, cystic fibrosis transmembrane conductance regulator cftr gene replacement during the neonatal period can decrease morbidity and mortality from cystic fibrosis cf. Gene therapy has the potential to control a broad range of diseases, including cystic fibrosis, heart diseases, diabetes, cancer, and blood diseases. Cystic fibrosis is one of the most common genetic conditions in the world, and has always been at the forefront of gene therapy research. Cystic fibrosis is a common severe autosomal recessive genetic disease which is caused by dysfunction of an epithelial cell surface camp activated c. Another option for treatment would be to give a person with cf the active form of the protein product that is scarce or missing.
The baby born with cf has normal lungs at birth, but evidence of inflammation and lung changes are present as early as 4 weeks of age. Cystic fibrosis is a genetic condition caused by a mutated gene called cftr. Frontiers gene therapy for cystic fibrosis lung disease. The effects of this dysfunction are pleoitropic but the human morbidity results from the effects in the respiratory epithelium. Gene therapy, introduction of a normal gene into an individuals genome in order to repair a mutation that causes a genetic disease. Cystic fibrosis cf is a multiorgan recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene. Cystic fibrosis cystic fibrosis cf is the most common, lifeshortening genetic disease in caucasians. Direct delivery of the cystic fibrosis transmembrane conductance regulator cftr gene to airway epithelia may offer advantages, as the tissue is accessible for topical delivery of vectors. A variety of cystic fibrosis gene therapy approaches based on viral adenovirus, retrovirus, and adenoassociated virus and nonviral liposomes and receptormediated endocytosis routes are. Cystic fibrosis is caused by mutations in the gene responsible for producing the cystic fibrosis transmembrane conductance regulator cftr protein. Emerging therapeutic approaches for cystic fibrosis. When there is a mutation or alteration in the genetic instructions, the production of the cftr protein may be affected. First, there seem to be two critical periods during which cftr mice are at greatest risk perinatally,2 one within the first few days after birth, and a subsequent period at weaning about 20 days of age.
At present, neither gene therapy nor any other kind of treatment exists. Gene therapy for cystic fibrosis cystic fibrosis is caused by mutations in the gene responsible for producing the cystic fibrosis transmembrane conductance regulator cftr protein. Gene therapy for cystic fibrosis proceedings of the. Five years ago it was shown that nucleasedependent gene editing could correct the most common cfcausing mutation p. Cystic fibrosis is a common severe autosomal recessive genetic disease which is caused by dysfunction of an epithelial cell surface camp activated ci channel. Adenovirus based vectors have been usedto introducehumancftranda1antitrypsin cdnas. Today, researchers struggle to develop a safe, effective gene therapy, as well as other, more traditional therapies. As a result, patients suffer from blocked airways and bacterial infections. Choice of vector, mode of delivery to airways, translocation of genetic information, and sufficient expression level of the normalized cftr gene are. But scientists hope that the technologies being developed for lung cells will be adapted to treat other organs affected by cf.
Phe508del legacy name f508del 1 and restore the function. Gene therapy for cf the cftr gene, mutations of which result in cf, was discovered in 1989. It is the most common type of chronic lung disease in children and young adults, and may result in early death. Because cf lung disease is currently the major cause of mortality and morbidity, and the lung airway is readily accessible to gene delivery, the major cf gene therapy effort at present is directed to the lung. Pdf gene therapy is being developed as a novel treatment for cystic fibrosis cf, a condition that has hitherto been widelyresearched yet for which.
Gene therapy for cystic fibrosis journal of clinical investigation. Adenovirus based vectors have been usedto introducehumancftranda1antitrypsin cdnas into the lung epithelium of cotton rats. Advances in gene therapy for cystic fibrosis lung disease. It affects the transport of salt and water across cells and affects different organs, but lung disease is responsible for the majority of symptoms, burden of care, and lost years of life. Since cf is a genetic disease, the only way to prevent or cure it would be with gene therapy at an.
For those with cystic fibrosis who have certain gene mutations, doctors may recommend cystic fibrosis transmembrane conductance regulator ctfr modulators. Cystic fibrosis centers for disease control and prevention. As yet little is known of psychological aspects of gene therapy. New approaches to genetic therapies for cystic fibrosis journal of.
If this observation is reproducible, it could herald a new and effective treatment for the gastrointestinal pathology associated with cystic fibrosis, although any. In people with cystic fibrosis, mutations in the cftr gene can result in no protein, not enough protein, or a protein being made incorrectly. Ideally, gene therapy could repair or replace the defective gene. Cystic fibrosis gene therapy in the uk and elsewhere uta griesenbach, kamila m. This pilot study aimed to investigate the attitudes, expectations, knowledge and psychological functioning of participants in a. Cystic fibrosis is a genetic disease that causes mucus to build up in a patients lungs. Learn about approaches to and issues surrounding gene therapy. Overcoming the cystic fibrosis sputum barrier to leading.
Cystic fibrosis results from deleterious genetic variants in the cftr gene, which encodes for the cystic fibrosis transmembrane conductance regulator cftr protein. Cystic fibrosis cf is an inherited monogenic disorder, amenable to gene based therapies. Theoretically, cystic fibrosis transmembrane conductance regulator cftr gene replacement during the neonatal period can decrease morbidity and mortality from cystic fibrosis cf. Gene therapy tools are currently being used for wide range of monogenic and multigenic disorders including but not limited to cystic fibrosis. The sweat glands and the reproductive system are also usually involved. They may improve lung function and weight, and reduce the amount of salt in sweat. Firstly, it isnt permanent since epithelial cells for example have a short life and are constantly being renewed, so the treatment would have to be performed regularly and this would be expensive. Cystic fibrosis cf is a progressive, chronic and debilitating genetic disease caused by mutations in the cf transmembraneconductance regulator cftr gene. Advances made with delivery vehicles for gene therapy can inform development of delivery vehicles for gene editing.
In the human cf lung, inhaled gene vectors must penetrate the viscoelastic secretions coating the airways to reach target cells in the underlying epithelium. While treatment advances have increased the life expectancy of patients, most of them only live to. We investigated whether cf sputum acts as a barrier. Theres no cure for cystic fibrosis, but a range of treatments can help control the symptoms, prevent or reduce complications, and make the condition easier to live with. New approaches to genetic therapies for cystic fibrosis. Cystic fibrosis was really at that moment the prototype disease to be used for gene therapy, says marianne carlon, a gene therapy researcher at catholic university in leuven, belgium. Cystic fibrosis cf is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr.
Cystic fibrosis cf is an autosomal recessive disease caused by mutations of the cftr gene, which encodes a member of the adenosine triphosphate. Find out more about how gene editing could help people with cystic fibrosis cf and the work the cystic fibrosis trust is funding in this area. Apr 01, 2015 the cystic fibrosis transmembrane conductance regulator cftr gene was identified in 1989. Cystic fibrosis cf is one of the most common fatal hereditary diseases. While treatment advances have increased the life expectancy of patients, most of them only live to the. This opened the door for the development of cystic. Gene therapy offers great promise for cystic fibrosis which has never been quite fulfilled due to the challenges of delivering sufficient amounts of the cftr gene and expression persistence for a sufficient period of time in the lungs to have any effect. While life expectancy has improved, current treatments for cf are neither preventive nor curative. Cystic fibrosis transmembrane conductance regulator mutations are categorized into 6 classes based on the mutation function or protein output 5. This opened the door for the development of cystic fibrosis cf gene therapy, which has been actively pursued for the last 20 years. Cystic fibrosis what is cystic fibrosis cystic fibrosis cf is a chronic, progressive.
Gene therapy for cystic fibrosis cf is the introductionaddition of normal wildtype copy of the cftr geneallele to the genome of a personorganism carrying defectiveabnormal copies of the gene, done so for the purpose of compensating for the abnormal gene or replacing proteins that the patient cannot produce. Gene therapy for children with cystic fibrosiswho has the. Sep 29, 2004 gene therapy is currently being evaluated for a wide range of acute and chronic lung diseases including acute respiratory distress syndrome ards, cancer, asthma, emphysema and cystic fibrosis. The principal cause of morbidity and mortality in cystic fibrosis cf is pulmonary disease, so the focus of new treatments in this condition is primarily targeted at the lungs. Cystic fibrosis cystic fibrosis is an inherited disease that causes thick, sticky mucus to build up in the lungs and digestive tract. By 1993, gene therapy trials to treat people with cf began. Pdf gene therapy for the treatment of cystic fibrosis researchgate. The cftr gene was identified in 1989, touching off a wave of enthusiasm for developing a gene therapy cure for the disorder. Nov 07, 2018 cystic fibrosis cf is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene that encodes a campregulated anion channel.
Pdf lentiviral vectors and cystic fibrosis gene therapy. We have several points to raise about larson and colleagues1 report. Although cystic fibrosis cf seems a good candidate for gene therapy gt, 15 years of intense investigations and a number of clinical trials have not yet produced a viable clinical. Gene therapy, which is the transfer of genetic materials into the cells for therapeutic purposes, holds a huge promise in treating various hereditary diseases. Cystic fibrosis cf is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr gene that encodes a campregulated anion channel. Ideally, future novel treatments such as gene therapy. Pathogenesis and future treatment strategies felix a ratjen md phd frcpc introduction pathophysiology genetics cystic fibrosis transmembrane regulator function airway surface liquid and mucociliary clearance infection and inflammation new therapies cystic fibrosis transmembrane regulator replacement therapy. If this observation is reproducible, it could herald a new and effective treatment for the gastrointestinal pathology associated with cystic fibrosis.
W h colledge, m j evans, cystic fibrosis gene therapy, british medical bulletin, volume 51, issue 1, january 1995, pages 8290. Cystic fibrosis cf is a common, lethal, genetic disease and is caused by mutations in the cystic fibrosis transmembrane conductance regulator cftr. Researchers have, for the first time, managed to successfully smuggle healthy copies of genes into the lungs of people with cystic fibrosis. A new partnership in the uk will develop a gene therapy for cystic fibrosis that could treat the disease with a single dose. Phe508del legacy name f508del 1 and restore the function of the cftr. Gene therapy offers great promise for cystic fibrosis which has never been quite fulfilled due to the chal lenges of delivering sufficient amounts. Cystic fibrosis cf is a disease characterized by airway infection, inflammation, remodeling, and obstruction that gradually destroy the lungs. Yet, physical and host immune barriers in the lung.
These have largely been single dose to either nose or lower airway and have been designed around. Cystic fibrosis diagnosis and treatment mayo clinic. Towards gene therapy for cystic fibrosis british society. These newer medications help improve the function of the faulty cftr protein. Cf pri marily affects the respiratory and digestive systems in children and young adults. Some strategies are mutation specific and have already reached clinical development. While life expectancy has improved, current treatments for cf are. The discovery of the cystic fibrosis transmembrane conductance regulator cftr gene 25 years ago set the stage for unraveling the pathogenesis of cf lung disease, continuous refinement of symptomatic treatments and the development of mutationspecific therapies, which are now becoming available for a subgroup of. Gene therapy involves the transfer of correct copies of cystic fibrosis transmembrane conductance regulator cftr dna. Stem cells for cystic fibrosis therapy cf foundation.
The report of the first patients with cystic fibrosis cf to receive cystic fibrosis transmembrane conductance regulator gene cftr therapy appeared in 1993, and since then there have been more than 20 clinical trials of both viral and nonviral gene transfer agents. The baby born with cf has normal lungs at birth, but evidence of inflammation and lung changes. In 1989, the gene causing cystic fibrosis cf was discovered. I was intrigued by larson and colleagues claim march 1, p 6191 that they have reversed the cystic fibrosis phenotype in mice by transient infection with a cystic fibrosis transmembrane receptor cftr adenoviral vector in utero. Cystic fibrosis cf is an inherited monogenic disorder, amenable to genebased therapies. Since the discovery of the gene encoding cystic fibrosis cf, there has been much excitement about the possibility of gene therapy, which has now reached the stage of phase i clinical trials in adults. Prospects for gene therapy in cystic fibrosis archives. Also, since cystic fibrosis is a disease that affects the entire body, it isnt possible to treat everything, and while. Transmembrane conductance regulator cftr gene on the long arm of chromosome 7. Cystic fibrosis is the lethal inherited disease that effects lungs pancreas sweat glands characterized by the production of abnormally viscous mucus by the affected glands fibrous scar tissue develops in the pancreas. The report of the first patients with cystic fibrosis cf to receive cystic fibrosis transmembrane conductance regulator gene cftr therapy appeared in 1993, and since then there have been more t. The discovery of the cystic fibrosis transmembrane conductance regulator cftr gene 25 years ago set the stage for unraveling the pathogenesis of cf lung disease, continuous refinement of symptomatic treatments and the development of mutationspecific therapies, which are now becoming. Unfortunately, larsons report does not tell us the percentage of the cftr and lacz treated mice that survived these.
In july 2015, the results of an eagerly anticipated clinical trial of gene therapy in cystic fibrosis were published alton et al. With improvements in nutritional therapy, antibiotics, and chest phys. The problems with either of the methods of gene therapy are twofold. An improved understanding of the cystic fibrosis cf transmembrane conductance regulator cftr protein structure and the consequences of cftr gene mutations have allowed the development of novel therapies targeting specific defects underlying cf. Clinical trials have already been performed using cationic liposome and adenoviral based gene transfer systems. Delivering on the promise of gene editing for cystic fibrosis.
Yet, physical and host immune barriers in the lung present. Since the cloning of the cystic fibrosis transmembrane conductance regulator cftr gene in 1989, there has been significant interest in the possibility of gene therapy as a treatment for cf. The first cystic fibrosis gene therapy experiments have involved lung cells because these cells are readily accessible and because lung damage is the most common, lifethreatening problem in cf patients. Gene therapy for treatment of the cystic fibrosis lung has been an active area of research. The cystic fibrosis transmembrane conductance regulator cftr gene contains the instructions for making the cftr protein. Cystic fibrosis cf is an autosomal recessive disease caused by mutations in the cf transmembrane regulator cftr gene and is the most common lifeshortening genetic defect in caucasians. Gene therapy in cystic fibrosis archives of disease in. The report of the first patients with cystic fibrosis cf to receive cystic fibrosis transmembrane conductance regulator gene cftr therapy. New gene therapy could treat cystic fibrosis with one dose. Cystic fibrosis what is cystic fibrosis cystic fibrosis cf is a chronic, progressive, and frequently fatal genetic inherited dis ease of the bodys mucus glands.
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