Pitt Innovation Challenge 2020
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A novel set of lung-targeting peptides, applied to deliver siRNAs to treat the lungs of patients with Cystic Fibrosis.
- Therapies for Cystic Fibrosis (CF), a common chronic lung disease leading to repeated infections and ultimately need for lung transplantation, cannot penetrate through the thick mucus and effectively target lung tissue.
- We have identified two novel lung-targeting peptides that are taken up by lungs specifically in as little as 15 minutes after a peripheral intravenous injection.
- These novel, patent-pending, lung-targeting peptides can deliver small interfering RNA (siRNA) to the lungs to knockdown chaperone proteins that degrade the faulty protein seen in patients with CF.
- This approach would allow treatment of CF patients with all sorts of different genetic mutations and not just the most common mutation, as is the case with current disease modifying therapies.
- This would open up avenues for treatment of other lung diseases like interstitial lung disease by simply swapping out the siRNA and targeting other pathways at play in these diseases.
CF is the most common autosomal recessive, life-limiting genetic disorder in the Caucasian population, affecting 1 in 2000-to-3000 live births. In the era of modern medicine, the median survival is 39.3 years according to Cystic Fibrosis Foundation 2014 registry reports.
Targeted therapies for the lung have not been possible due to lack of appropriate vectors, even though there are two ways to deliver drugs to the lungs-inhaled vapors and injection into the blood stream. Inhaled therapies in CF are difficult due to entrapment of drugs in the thick mucus layer.
Our lung-targeting peptides would allow for peripheral injections leading to drug uptake by lung epithelial tissue. As these peptides are simply vectors that can carry many different therapeutics, they are platform technology, and proof of principal studies with one therapeutic will open up doors for other potential therapeutics, not just in CF, but other chronic lung diseases, like interstitial lung fibrosis.
Cell penetrating peptides are small, 5-30 amino acid long peptides, that are either naturally occurring or synthetic, and are capable of crossing cell membrane barriers while carrying cargoes much larger than themselves. Our work has identified two, 12-amino acid long peptides, that target the lung tissue specifically in as little as 15 minutes.
Our proposal is to test these peptides as novel vectors to deliver siRNA targeting a chaperone protein that would normally destroy the mutant channel protein in CF. By diminishing the production of the protein, the mutant CF protein would be saved, and hence have increased levels in cell and function. Additionally, this would be usable in CF patients with all types of mutations. These proof of concept studies would not only introduce a new treatment for CF but also open up avenues for other peptide or even whole protein-based therapies for CF.
The competitive landscape analysis below summarizes key features of this solution, and current competitors working to solve similar healthcare problems.
- Maliha Zahid, MD, PhD, Assistant Professor, Department of Developmental Biology. Expertise in lung-targeting peptides and cell penetrating peptides.
- Raymond Frizzell, PhD, Professor, Department of Pediatrics, Director Center for Excellence in Cystic Fibrosis. Expertise in CF genetics and cellular physiology.
- Sanjay Mishra, PhD, Staff Scientist. Expertise in cell biology specifically as it relates to CF.
- Milestone 1: Successful loading of the two lung-targeting peptides with small interfering RNA directed to the key chaperone protein, and showing successful entry into lung cells.
- Milestone 2: Assessing improvement in the mutant CF protein by introducing peptide+siRNA into lung cells from CF patients.
- Milestone 3: Treatment of CF-mutant mice with weekly intravenous lung-targeting peptide+siRNA, and novel assessment of improvement in lung clearances over a 12-week period.
Path to Impact Plan
Our plan is to generate high quality data and reproduce it, which would lead to an abstract to be presented at high visibility national or international lung meetings, as well as generation of a manuscript to be published in the highest impact factor, peer-reviewed clinical journal. We also hope to leverage this work to obtain substantial NIH funding to reproduce our work in larger animal models of CF, ultimately leading to toxicity studies in two vertebrate species (one rodent, one non-rodent) to ultimately lead to a Phase I human study IND approval from the FDA. Upon reaching that milestone, we would seek industry partners to advance the science in developing a targeted treatment for CF.
Frequently Asked Questions
How innovative is this technology?
These lung-targeting peptides are patent pending, never before reported, unique, synthetic cell penetrating peptides. Currently there are no cell penetrating peptides for lung reported in the literature.
Is this project early stage?
Yes, it is early stage but all of the pieces for proof of concept are in place and available. These proof of concept studies would not only open other therapies for CF but also open avenues for other chronic lung diseases.
What is the advantage of using lung-targeting peptides over viral vectors?
Viral vectors can incite an immune response and cause inflammation as well as interfere with repeat therapies. No immune responses have been reported to cell penetrating peptides.
What other diseases could lung-targeting peptides be used for?
Lung-targeting peptides are platform technology and vectors that can be used to deliver many different therapies like drugs, peptides, proteins, and other siRNA. Therefore, they could be used to deliver therapies in other chronic lung conditions like interstitial lung fibrosis and chronic obstructive pulmonary disease.