Overcoming Barriers of Gene Therapy for Cystic Fibrosis
Genetic diseases involve problems with the functioning genes that we each inherit. Gene therapy intends to compensate for genetic defects or mutations by introducing a copy of the genes that express functional proteins and correct or address the underlying cause of the disease. Gene therapy has the potential to treat all mutations, but requires delivery of genetic material to target cells, a key obstacle for cystic fibrosis gene therapy. Gene therapy is the only mutation-agnostic approach to treat cystic fibrosis.
Outcomes of gene therapy trials for cystic fibrosis and other genetic diseases throughout the 1990’s were disappointing. However, in recent years gene therapy has reached a tipping point, with treatments approved for metabolic disease, oncology, and immunodeficiency since 2012, and a variety of others in clinical development. The most recent gene therapy trial for cystic fibrosis was conducted in 2015, in which treated patients showed an arrest of disease progression, indicating the promise of the approach – but results continue to be modest. The general consensus for the modest impact of current gene therapy approaches for cystic fibrosis, and many other diseases, is the limited ability of the vectors to effectively and efficiently deliver their genetic payload. In the case of cystic fibrosis specifically, it is the ability of a vector to effectively and efficiently deliver functional cystic fibrosis transmembrane conductance regulator (CFTR).
Talee has two proprietary technologies that are designed to address this critical limitation, an adeno-associated viral gene therapy platform and a lentiviral gene therapy platform. Each has the ability to carry a large payload and, therefore, to overcome the biggest limitation to using gene therapy to treat cystic fibrosis.
Cystic Fibrosis - The Disease
Cystic fibrosis is a life-threatening, autosomal recessive genetic disease with no cure. Cystic fibrosis is caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Derangement of CFTR interferes with mucociliary transport and antibacterial activity in the airways and gut and causes a buildup of mucous and susceptibility to airway infections that is ultimately lethal.
Cystic fibrosis is primarily characterized by progressive airway infection and inflammation, and, in the majority of individuals, death from respiratory failure. The annual incidence is approximately 1,000 in the US, with an estimated prevalence of 70,000 worldwide.
Current Treatment Options
The standard of care for cystic fibrosis includes therapies that address symptoms of the disease, such as bronchodilators, mucolytics, and antibiotics, and those that attempt to modulate the activity of defective CFTR, such as correctors of CFTR trafficking or potentiators of impaired ion channel activity. None of the current treatments prevent continued disease progression and many have efficacy in only a subset of cystic fibrosis -causative mutations.
Given the limitations of current cystic fibrosis treatments, gene therapy has the potential to offer a universal cure.
Technology Overview
Talee has developed a novel transgene and a number of innovations in multiple viral vectors that collectively will overcome challenges that have previously limited the clinical viability of gene therapy for cystic fibrosis. Currently, Talee has two proprietary technologies, an adeno-associated (AAV) viral gene therapy platform and a lentiviral gene therapy platform. Each has been developed to be highly tropic to human airway epithelia and, therefore, to overcome the biggest limitation to using gene therapy to treat or cure cystic fibrosis.
Each of these technologies improves how well the gene therapy can deliver the normal gene to lung cells and how well the lung cells can make the replacement protein.
AAV Platform
Our AAV platform is designed to solve several key issues that are holding back gene therapy treatment for cystic fibrosis. As such, it includes the following elements:
- a highly functional CFTR minigene (CFTRΔR),
- a highly active synthetic promoter (SP183) that drives high-level CFTR expression,
- augmenters to significantly enhance AAV transduction by overcoming barriers of nuclear uptake in human airway epithelia, and
- an evolved chimeric AAV vector that is highly tropic for the human airway (AV.TL65).
Lentivirus Platform
Our lentiviral platform is a modified lentiviral vector technology that has the benefits of a large carrying capacity, high transduction efficiency, persistent expression, minimal immunogenicity, and genomic integration, thereby allowing transduced progenitor cells to indefinitely produce corrected airway epithelia without oncogenic risk. The vector is genetically engineered with an envelope protein which increases binding and entry to the surface of airway epithelial cells.
Because it can effectively deliver large payloads without causing debilitating immune reactions, and because it integrates into the genome with minimal risk of genotoxicity, our lentiviral-based gene therapy treatment has the potential to be a single administration, long-lasting genetic treatment for cystic fibrosis.
Manufacturing
Talee is taking a multi-pronged approach to producing our products. We are utilizing the manufacturing facilities and expertise of our partners at the Children’s Hospital of Philadelphia (CHOP) and the University of Iowa and we are building our own in-house expertise and capability. Both the CHOP and Iowa facilities have been used successfully in numerous gene therapy clinical trials.