For the treatment of cystic fibrosis, RNA medicines, gene transfer therapies, and gene editing treatments have potential

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Acid Treatment ◽  
Gene Editing ◽  
Healthy Adult ◽  
Phase 1 ◽  
Clinical Settings ◽  
Potential Harm ◽  
Cohesive Group

Many unique genetic procedures have been created to reach the heart of the cystic fibrosis (CF) problem, overcoming a defective gene, and advances in the nucleic acid treatment industry have made these methods much more viable as potential remedies. However, before any of these approaches can be used in clinical settings, a number of hurdles must be overcome, including determining which organs should be targeted for the most robust effect with the least amount of potential harm; determining which cells should be targeted in each organ; and determining what constitutes a successful treatment. Another factor to consider is that, unlike many other treatments, gene therapy and gene editing will need advancing clinical trials ahead without data from healthy adult control cohorts; rather, phase 1 studies will require CF patients. Furthermore, we must select which patients should be included in the initial studies for mutation-agnostic methods: should we include all patients, even if effective modulator therapy is available? Clearly, if we are to be successful, we will have to face some significant challenges, and we will have to do it as a cohesive group, as we have always done.

scholarly journals Not as easy as it looks: Gene therapy for cystic fibrosis

2008 ◽  
Vol 30 (3) ◽  
pp. 22-25
Author(s):  
Tim Lee ◽  
Eric Blair
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Respiratory Tract ◽  
Low Levels

The gene responsible for cystic fibrosis (CF) was first identified in 1989. Since that time, gene therapy has held the promise of a cure for cystic fibrosis; however, progress has been much slower than initially hoped. Clinical trials of gene therapy have demonstrated that the corrected CF gene can be expressed successfully in the respiratory tract of subjects with CF, but only for approximately 30 days at best, and at low levels.

scholarly journals Alzheimer’s disease: An overview of the current treatments

Bionatura ◽  
2019 ◽  
Vol 02 (Bionatura Conference Serie) ◽  
Author(s):  
Carolina Serrano-Larrea ◽  
David Clavijo-Calderón
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Nerve Growth Factor ◽  
Phase 1 ◽  
Phase 2 ◽  
Adeno Associated Virus ◽  
The World ◽  
Phase 2 Clinical Trials

Alzheimer’s disease (AD) affects millions of people around the world and although there are treatments that help control symptoms and slow down the progress of the disease, there is still no cure. Current treatments include three acetylcholine inhibitors, a glutamate inhibitor and a combination of the two. Due to the failure of hundreds of clinical trials with monotherapies, multitarget treatments are currently being investigated that consider both brain and peripheral factors. Gene therapy is one of the most promising therapies to treat and prevent the development of AD. Nowadays, there is no available medical treatment based on gene therapy to treat AD; however, there are treatments in phase 1 and phase 2 clinical trials with promising results. In this review, we will focus on the most important gene therapy treatments, CERE-110 (adeno-associated virus AAV2-Nerve Growth Factor), Intracerebral AAV gene delivery of APOE2 and gene therapy using PPARγ-coactivator-1α(PGC-1α)

scholarly journals Ocular Gene Therapy with Adeno-associated Virus Vectors: Current Outlook for Patients and Researchers

2020 ◽  
Author(s):  
Geoffrey A. Casey ◽  
Kimberly M. Papp ◽  
Ian M. MacDonald
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Editing ◽  
Gene Replacement ◽  
Adeno Associated Virus ◽  
Virus Vectors ◽  
Gene Therapies ◽  
Ocular Disorders ◽  
Adenoassociated Virus ◽  
Underlying Mechanisms

In this “Perspective”, we discuss ocular gene therapy – the patient’s perspective, the various strategies of gene replacement and gene editing, the place of adenoassociated virus vectors, routes of delivery to the eye and the remaining question - “why does immunity continue to limit efficacy?” Through the coordinated efforts of patients, researchers, granting agencies and industry, and after many years of pre-clinical studies, biochemical, cellular, and animal models, we are seeing clinical trials emerge for many previously untreatable heritable ocular disorders. The pathway to therapies has been led by the successful treatment of the RPE65 form of Leber congenital amaurosis with LUXTURNATM. In some cases, immune reactions to the vectors continue to occur, limiting efficacy. The underlying mechanisms of inflammation require further study, and new vectors need to be designed that limit the triggers of immunity. Researchers studying ocular gene therapies and clinicians enrolling patients in clinical trials must recognize the current limitations of these therapies to properly manage expectations and avoid disappointment, but we believe that gene therapies are well on their way to successful, widespread utilization to treat heritable ocular disorders.

scholarly journals TALEN-Mediated Gene Targeting for Cystic Fibrosis-Gene Therapy

Genes ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 39 ◽  
Author(s):  
Emily Xia ◽  
Yiqian Zhang ◽  
Huibi Cao ◽  
Jun Li ◽  
Rongqi Duan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Gene Editing ◽  
Airway Epithelial Cells ◽  
In Vivo Studies ◽  
Cystic Fibrosis Gene ◽  
Lacz Reporter ◽  
Gene Correction ◽  
Transcription Activator ◽  
Stringent Requirement

Cystic fibrosis (CF) is an inherited monogenic disorder, amenable to gene-based therapies. 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. Although airway epithelial cells are renewed slowly, permanent gene correction through gene editing or targeting in airway stem cells is needed to perpetuate the therapeutic effect. Transcription activator-like effector nuclease (TALEN) has been utilized widely for a variety of gene editing applications. The stringent requirement for nuclease binding target sites allows for gene editing with precision. In this study, we engineered helper-dependent adenoviral (HD-Ad) vectors to deliver a pair of TALENs together with donor DNA targeting the human AAVS1 locus. With homology arms of 4 kb in length, we demonstrated precise insertion of either a LacZ reporter gene or a human cystic fibrosis transmembrane conductance regulator (CFTR) minigene (cDNA) into the target site. Using the LacZ reporter, we determined the efficiency of gene integration to be about 5%. In the CFTR vector transduced cells, we were able to detect CFTR mRNA expression using qPCR and function correction using fluorometric image plate reader (FLIPR) and iodide efflux assays. Taken together, these findings suggest a new direction for future in vitro and in vivo studies in CF gene editing.

scholarly journals Taking Gene Therapy into the Clinic

2003 ◽  
Vol 2003 (1) ◽  
pp. 71-77 ◽  
Author(s):  
Daniel H. Palmer ◽  
Ming-Jen Chen ◽  
David J. Kerr
Keyword(s):  
Colorectal Cancer ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Gene Targeting ◽  
Treatment Strategy ◽  
Phase 1 ◽  
Therapeutic Benefit ◽  
Cancer Treatments ◽  
Novel Treatment

Gene therapy represents a promising novel treatment strategy for colorectal cancer. Preclinical data has been encouraging and several clinical trials are underway. Many phase 1 trials have proven the safety of the reagents but have yet to demonstrate significant therapeutic benefit. Ongoing efforts are being made to improve the efficiency of gene delivery and accuracy of gene targeting with the aim of enhancing antitumor potency. It is envisaged that gene therapy will be used in combination with other therapies including surgery, chemotherapy, and radiotherapy to facilitate the improvements in cancer treatments in the future.

scholarly journals Lentiviral Vectors for the Treatment and Prevention of Cystic Fibrosis Lung Disease

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 218 ◽  
Author(s):  
Laura Marquez Loza ◽  
Eric Yuen ◽  
Paul McCray
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Insertional Mutagenesis ◽  
Primary Cultures ◽  
Severe Combined Immunodeficiency ◽  
Lentiviral Vectors ◽  
Retroviral Vectors ◽  
Airway Epithelia

Despite the continued development of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs for the treatment of cystic fibrosis (CF), the need for mutation agnostic treatments remains. In a sub-group of CF individuals with mutations that may not respond to modulators, such as those with nonsense mutations, CFTR gene transfer to airway epithelia offers the potential for an effective treatment. Lentiviral vectors are well-suited for this purpose because they transduce nondividing cells, and provide long-term transgene expression. Studies in primary cultures of human CF airway epithelia and CF animal models demonstrate the long-term correction of CF phenotypes and low immunogenicity using lentiviral vectors. Further development of CF gene therapy requires the investigation of optimal CFTR expression in the airways. Lentiviral vectors with improved safety features have minimized insertional mutagenesis safety concerns raised in early clinical trials for severe combined immunodeficiency using γ-retroviral vectors. Recent clinical trials using improved lentiviral vectors support the feasibility and safety of lentiviral gene therapy for monogenetic diseases. While work remains to be done before CF gene therapy reaches the bedside, recent advances in lentiviral vector development reviewed here are encouraging and suggest it could be tested in clinical studies in the near future.

scholarly journals Potential of helper-dependent Adenoviral vectors in CRISPR-cas9-mediated lung gene therapy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ranmal Avinash Bandara ◽  
Ziyan Rachel Chen ◽  
Jim Hu
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Lung Disease ◽  
Viral Vectors ◽  
Gene Editing ◽  
Genetic Diseases ◽  
Adenoviral Vectors ◽  
The Status

AbstractSince CRISPR/Cas9 was harnessed to edit DNA, the field of gene therapy has witnessed great advances in gene editing. New avenues were created for the treatment of diseases such as Cystic Fibrosis (CF). CF is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Despite the success of gene editing with the CRISPR/Cas9 in vitro, challenges still exist when using CRISPR/Cas9 in vivo to cure CF lung disease. The delivery of CRISPR/Cas9 into lungs, as well as the difficulty to achieve the efficiency required for clinical efficacy, has brought forth new challenges. Viral and non-viral vectors have been shown to deliver DNA successfully in vivo, but the sustained expression of CFTR was not adequate. Before the introduction of Helper-Dependent Adenoviral vectors (HD-Ad), clinical trials of treating pulmonary genetic diseases with first-generation viral vectors have shown limited efficacy. With the advantages of larger capacity and lower immunogenicity of HD-Ad, together with the versatility of the CRISPR/Cas9 system, delivering CRISPR/Cas9 to the airway with HD-Ad for lung gene therapy shows great potential. In this review, we discuss the status of the application of CRISPR/Cas9 in CF gene therapy, the existing challenges in the field, as well as new hurdles introduced by the presence of CRISPR/Cas9 in the lungs. Through the analysis of these challenges, we present the potential of CRISPR/Cas9-mediated lung gene therapy using HD-Ad vectors with Cystic Fibrosis lung disease as a model of therapy.

scholarly journals Innovative therapies in genetic diseases: Cystic fibrosis

2021 ◽  
Vol 70 (1) ◽  
pp. 16-20
Author(s):  
Elena-Silvia Shelby ◽  
◽  
Florina Mihaela Nedelea ◽  
Tanser Huseyinoglu ◽  
Relu Cocos ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Antisense Oligonucleotides ◽  
Viral Vectors ◽  
Genetic Diseases ◽  
Wild Type ◽  
Gene Encoding ◽  
Innovative Therapies ◽  
Type Gene

Cystic fibrosis, also named mucoviscidosis, is the most frequent hereditary pulmonary disease and is produced by mutations in the CFTR gene, encoding an anionic channel for chloride and bicarbonate involved in the regulation of salt and bicarbonate metabolisms. Currently, about half of the patients with cystic fibrosis can benefit personalized therapy consisting in modulators, drugs which restore or improve the functionality and stability of CFTR. Moreover, presently, other therapies, such as gene therapy using the CRISP/CAS-9, modified antisense oligonucleotides or the insertion of the wild-type gene using nanolipidic particles or viral vectors, are being developed. This article aims to take stock of the principal types of cystic fibrosis therapies which have been approved or are in clinical trials.

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