Gene Therapy (4D-710) for Cystic Fibrosis
(CF Trial)
Recruiting in Palo Alto (17 mi)
+16 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: 4D Molecular Therapeutics
Must be taking: CFTR modulators
Must not be taking: Systemic corticosteroids, Immunosuppressants
Disqualifiers: Diabetes, Mycobacterium, Aspergillosis, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new gene therapy called 4D-710 in adults with cystic fibrosis who can't use standard treatments. The goal is to see if it is safe and effective. 4D-710 is part of a new generation of AAV vectors being developed for cystic fibrosis gene therapy.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you are on CFTR modulator therapy, you must continue it throughout the study.
What data supports the effectiveness of the treatment 4D-710 for cystic fibrosis?
Gene therapy for cystic fibrosis has shown promise in correcting the underlying genetic defect in laboratory settings, and similar approaches have been successful in other genetic diseases. Although specific data on 4D-710 is not provided, the success of gene therapy in other contexts suggests potential effectiveness.
12345Is 4D-710 gene therapy for cystic fibrosis safe for humans?
The safety of gene therapy for cystic fibrosis has been evaluated in various studies. In one study, a single dose was well tolerated but caused flu-like symptoms in some patients. Another study showed that repeated doses in sheep were well tolerated with no significant toxicity, suggesting potential safety in humans.
12367How is the treatment 4D-710 for cystic fibrosis different from other treatments?
4D-710 is a gene therapy specifically designed to address the underlying genetic cause of cystic fibrosis by delivering a functional copy of the CFTR gene to the lungs, which is different from traditional treatments that mainly manage symptoms rather than targeting the root cause.
128910Eligibility Criteria
Adults with cystic fibrosis who can't take CFTR modulator therapy or had bad reactions to it. They must be 18+, have certain genetic mutations, and their lung function should be within a specific range. People with recent serious infections, liver disease, diabetes not well controlled, or those on chronic steroids/immunosuppressants can't join.Inclusion Criteria
I have either two mutations in the CFTR gene or one mutation with CF lung symptoms.
I am 18 years old or older.
Sweat chloride ≥ 60 mmol/L
+4 more
Exclusion Criteria
I have not had gene therapy before, except for mRNA-based treatments.
I am being treated for a severe lung allergy with steroids or antifungal medication.
I am currently being treated for an active Mycobacterium abscessus infection.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single inhalational administration of 4D-710 at various dose levels
Single dose
Follow-up
Participants are monitored for safety and effectiveness after treatment
24 months
Participant Groups
The trial is testing a single dose of an investigational gene therapy called 4D-710 in adults with cystic fibrosis. It's an early-stage study (Phase 1/2) to see how safe the treatment is and how the body responds to it.
3Treatment groups
Experimental Treatment
Group I: 4D-710 Phase 2: Dose ExpansionExperimental Treatment1 Intervention
Participants will receive a single inhalational administration of 4D-710 at the dose level(s) selected for dose expansion.
Group II: 4D-710 Phase 1: Dose ExplorationExperimental Treatment1 Intervention
Participants who are ineligible for or intolerant of modulator therapy will receive one of various dose levels of 4D-710 to identify recommended phase 2 dose(s) for further evaluation.
Group III: 4D-710 Dose Exploration (Sub-Study)Experimental Treatment1 Intervention
Participants who are on currently available CFTR modulator therapy will receive a dose of 4D-710 at various dose levels.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Massachusetts General HospitalBoston, MA
University of Washington Medical CenterSeattle, WA
Virginia Commonwealth University Health SystemRichmond, VA
University of Kansas Medical CenterKansas City, KS
More Trial Locations
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Who Is Running the Clinical Trial?
4D Molecular TherapeuticsLead Sponsor
References
Gene therapy for cystic fibrosis: which postman, which box? [2019]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. Clinical trials have already been performed using cationic liposome and adenoviral based gene transfer systems, measuring the safety and efficacy of this new form of treatment, with variable results to date. These two approaches and the current progress in airway gene delivery are discussed.
Cystic Fibrosis Gene Therapy in the UK and Elsewhere. [2022]The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here.
Inhaled mRNA therapy for treatment of cystic fibrosis: Interim results of a randomized, double-blind, placebo-controlled phase 1/2 clinical study. [2023]MRT5005, a codon-optimized CFTR mRNA, delivered by aerosol in lipid nanoparticles, was designed as a genotype-agnostic treatment for CF lung disease.
Targeted therapies to improve CFTR function in cystic fibrosis. [2022]Cystic fibrosis is the most common genetically determined, life-limiting disorder in populations of European ancestry. The genetic basis of cystic fibrosis is well established to be mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for an apical membrane chloride channel principally expressed by epithelial cells. Conventional approaches to cystic fibrosis care involve a heavy daily burden of supportive treatments to combat lung infection, help clear airway secretions and maintain nutritional status. In 2012, a new era of precision medicine in cystic fibrosis therapeutics began with the licensing of a small molecule, ivacaftor, which successfully targets the underlying defect and improves CFTR function in a subgroup of patients in a genotype-specific manner. Here, we review the three main targeted approaches that have been adopted to improve CFTR function: potentiators, which recover the function of CFTR at the apical surface of epithelial cells that is disrupted in class III and IV genetic mutations; correctors, which improve intracellular processing of CFTR, increasing surface expression, in class II mutations; and production correctors or read-through agents, which promote transcription of CFTR in class I mutations. The further development of such approaches offers great promise for future therapeutic strategies in cystic fibrosis.
Gene therapy for the respiratory manifestations of cystic fibrosis. [2012]Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The major manifestations are on the airway epithelial surface, with purulent mucus, recurrent infections, chronic inflammation, and loss of lung function. Consequent to mutations in both parental genes, airway epithelial cells have insufficient CFTR function. Because this can be corrected in vitro by transfer of the normal CFTR gene into airway epithelial cells, it is reasonable to hypothesize that the respiratory manifestations of CF could be prevented by transfer of the normal human CFTR cDNA to the airway epithelium in vivo. Over the past 6 years, our laboratory has developed a strategy to accomplish this goal using a replication deficient E1-E3- recombinant adenovirus (Ad) serotype 5 vector containing the normal human CFTR cDNA (AdCFTR). Studies with experimental animals demonstrate that with administration of such a vector to the airways, the human CFTR cDNA could be transferred to the airway epithelium, with expression of the human CFTR cDNA for at least 6 weeks. Extensive preclinical studies in vitro and in vivo demonstrated that the risks to humans were sufficiently low to initiate a Phase I trial using the AdCFTR vector to treat the respiratory manifestations of CF in humans. Following approval by the National Heart, Lung, and Blood Institute Institutional Review Board, the National Institutes of Health Biosafety Committee, the National Institutes of Health Recombinant DNA Advisory Committee, and the Food and Drug Administration, we initiated the first human trial of gene therapy for CF on April 17, 1993. The clinical study is still ongoing, with safety and efficacy data being evaluated, but there is clear evidence that it is feasible to transfer and express the normal CFTR cDNA to the airway epithelium in vivo in individuals with CF.
The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep. [2022]Clinically effective gene therapy for Cystic Fibrosis has been a goal for over 20 years. A plasmid vector (pGM169) that generates persistent expression and reduced host inflammatory responses in mice has raised prospects for translation to the clinic. The UK CF Gene Therapy Consortium is currently evaluating long-term repeated delivery of pGM169 complexed with the cationic lipid GL67A in a large Multidose Trial. This regulatory-compliant evaluation of aerosol administration of nine doses of pGM169/GL67A at monthly intervals, to the sheep lung, was performed in preparation for the Multidose Trial. All sheep tolerated treatment well with no adverse effects on haematology, serum chemistry, lung function or histopathology. Acute responses were observed in relation to bronchoalveolar cellularity comprising increased neutrophils and macrophage numbers 1 day post-delivery but these increases were transient and returned to baseline. Importantly there was no cumulative inflammatory effect or lung remodelling with successive doses. Molecular analysis confirmed delivery of pGM169 DNA to the airways and pGM169-specific mRNA was detected in bronchial brushing samples at day 1 following doses 1, 5 and 9. In conclusion, nine doses of pGM169/GL67A were well tolerated with no significant evidence of toxicity that would preclude adoption of a similar strategy in CF patients.
Technology evaluation: cystic fibrosis therapy, Genzyme. [2017]Genzyme is developing therapies to replace the defective forms of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein in CF patients. The company is developing a gene therapy, as well as a recombinant production of CFTR for protein replacement therapy. Both approaches have been granted orphan drug status by the FDA [156348]. The results of several clinical trials were discussed at the first annual meeting of the American Society of Gene Therapy in May 1998. A single dose nasal administration was well tolerated by volunteers, but had disappointing efficacy. In a study completed at the Royal Brompton Hospital, London, a single dose aerosol application of GL-67:DOPE was administered to eight patients, while another eight received GL-67:DOPE plus pCF1-CFTR. In the second group, a moderate increase in the potential difference in the lung was observed, with a slight trend towards bacterial adherence normalization in the airway cells. Seven of the patients in the second group, and three patients who received lipid alone, developed, flu-like symptoms within 24 h. A trial at the University of Alabama, using the same formulation, showed that flu-like symptoms developed in six of eight patients by day two, and in all patients by day seven [290120]. In 1995, the company began a clinical safety trial involving delivery of a normal CF gene to the patient's lungs via an adenovirus vector. The administration involves the inhalation of an aerosol containing the vector or, separately, delivery to one lobe of the patient's lung via a bronchoscope [191678]. To evaluate additional delivery methods for the gene, Genzyme has an exclusive research agreement for the use of Vical's cytofectins as non-viral delivery vectors for CFTR. Also under investigation are delivery systems for the nasal epithelium using liposomes or lipid-DNA complexes. These protocols are being developed in collaboration with the National Heart & Lung Institute, London, and an undisclosed partner [162590], [177633]. Following in vitro screenings by the company, two T-shaped molecules were identified (GL-67 and GL-53), the gene transfer activities of which could be enhanced by dioleoyl-PE (DOPE). A recently-completed clinical trial in 16 CF patients demonstrated that the GL-67:DOPE:DMPE-PEG5000-pCF1-CFTR compound accumulated in the lung with minimal toxicity and resulted in a 25% correction of CF symptoms [268093]. Genzyme has also developed recombinant cell lines that synthesize CFTR and has used transgenic expression techniques to breed mice, rabbits and goats which secrete the protein in their milk. Protein replacement therapy is currently in preclinical investigation and research efforts have been reduced infavor of the gene therapeutic approach [177633].
Cystic fibrosis gene therapy. [2019]Cystic fibrosis is a common severe autosomal recessive genetic disease which is caused by dysfunction of an epithelial cell surface cAMP activated Cl- channel. The effects of this dysfunction are pleoitropic but the human morbidity results from the effects in the respiratory epithelium. Gene therapy is an attractive possible treatment, the gene required is well characterised and only low-level expression is required. The cellular target is accessible and the clinical effects of treatment should be readily assayable. This chapter reviews current proposals for suitable gene delivery mechanisms and vectors and discusses the clinical trials, the results from the first of which are now becoming available.
Gene therapy for cystic fibrosis: an example for lung gene therapy. [2020]Gene therapy is currently being evaluated for a wide range of acute and chronic lung diseases. The requirement of gene transfer into the individual cell types of the complex lung structure will very much depend on the target disease. Over the last decade, the gene therapy community has recognized that there is not even one vector that is good for all applications, but that the gene transfer agent has to be carefully chosen. Gene therapy is particularly attractive for diseases that currently do not have satisfactory treatment options and probably easier for monogenic disorders than for complex diseases. Cystic fibrosis (CF) fulfills these criteria and is therefore a good candidate for gene therapy-based treatment. This review will focus on CF as an example for lung gene therapy and discuss the progress made in this field over the last couple of years.
Recent progress in gene therapy for cystic fibrosis. [2012]Cystic fibrosis (CF) is a monogenic disorder and is therefore a good candidate for gene therapy. Initial clinical trials provided proof-of-principle for gene transfer to the airways, but efficiency was low and likely to be insufficient for clinical benefit. Here, we review the progress in CF gene therapy over the last 12 months, including recent advances in viral and non-viral gene transfer agents and novel strategies, such as RNA repair and stem cell gene therapy.