Nucleic Acid Nanoparticles for Treating Human Diseases
Cystic Fibrosis Program
Cystic fibrosis (CF) is the most common genetic disease in the Caucasian population in North American and Europe, with about 70,000 patients (30K patients in US and 40K in Europe). Presenting typically in early childhood, CF is caused by mutations in the CFTR gene, which encodes for a membrane-bound chloride channel. This aberration results in numerous symptoms, but the most dire complication is progressive lung failure, with median survivals in the third decade of life. Mutations in CFTR result in thick respiratory secretions, which result in recurrent lung infections, inflammation, structural damage, and progressive lung compromise.
The Copernicus approach to treating the lung manifestations of CF is to administer CFTR DNA NPs to the lung as an aerosol treatment (inhaled mist). Based on the efficient DNA nanoparticle (NP) uptake in proximal lung epithelial cells (cells lining the breathing tubes), the site of the disease process in CF patients, Copernicus initiated a CF NP drug development program. Based on favorable activity and safety in both normal and CF mice, Copernicus filed an IND application with the FDA to begin clinical testing of this approach. The initial Phase I multi-center trial dosed the nasal respiratory epithelium (the nose has cells similar to those in the lung airway) of CF subjects at three dose levels. We decided to initially administer our compound to respiratory cells in the nose, since this permits relatively easy testing of CFTR chloride channel function before and after dosing. Of 12 subjects participating in this trial, 8 had improvements in this test of CFTR function, with 4 having improvements within the normal range as defined by subjects without CF. CFTR improvements were observed in all three dose escalation cohorts. Importantly, no safety concerns arose from the use of NPs in the clinical trial. These encouraging results support further development of our CF lung therapy.
Since completion of this first Phase I CFTR DNA NP trial, Copernicus has completed the appropriate drug development steps to initiate a lung aerosol Phase I/II clinical trial in CF subjects. First, we demonstrated that DNA NPs are stable and highly active in the lungs of intubated rabbits following an aerosol (mist) dose of our therapeutic generated by one of several different commercial devices. Second, we modified our CFTR DNA NPs in two important ways, and both of these modifications are patented in the United States, Europe, and other foreign countries. We custom designed and optimized the actual DNA sequence of the human CFTR gene; the expressed CFTR protein is identical to normal, but its DNA sequence optimizes its level of expression. Next, we discovered an important DNA element that permits the human CFTR gene to be expressed at appropriate levels for the life time of the lung proximal epithelial cell in CF mice. This prolonged expression (PE) element is a short sequence of DNA that is specifically introduced into the DNA payload of our CFTR NPs. In multiple tests in CF mice, this element robustly permits the human CFTR gene to be expressed at clinically useful levels for months, and thereby is an important proprietary element in our CF intellectual property portfolio.
The proximal epithelial cells in our lungs have a limited lifespan of about 100 days, and then they die and are replaced by new epithelial cells derived from lung stem cells. This normal process of epithelial cell remodeling occurs essentially in all tissues that have epithelial cells, such as the lung, gut, kidney, and others. The new lung epithelial cells in patients with CF will not be expressing functional CFTR, and hence will need to be treated with Copernicus CFTR NPs. Our studies indicate that repeat dosing of CFTR NPs is quite effective, unlike viral vectors where repeat dosing is not effective due to production of neutralizing antibodies. The appropriate dose and interval of dosing will be the subject of future phase II CF clinical trials, although our current data provide considerable guidance for these pending trial results.