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Pharmacoengineering of advanced RNA-nanomedicines to treat cystic fibrosis (CF)

  • Full or part time
    Prof S Cryan
    Prof A Heise
    Prof C Greene
  • Application Deadline
    Monday, December 02, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

Cystic fibrosis (CF) is an inherited disorder caused by a mutation in a single gene responsible for the production of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR). While potentiator and corrector drugs have improved therapy for some CF patients, there remains an unmet need for advanced therapies to treat the significant number of patients who do not respond to these approaches. MicroRNAs have been found to play an important role in both inflammatory processes and in regulation of CFTR and we and others have determined that exogenous delivery of this microRNA to CF cells can attenuate inflammatory responses and therefore offer a promising new gene therapeutic strategy for CF1-2.

Respiratory drug delivery is a well-established means of treating respiratory disease and our team is developing technologies for local targeting of RNAi therapies to the CF lungs. CF was one of the first diseases targeted for gene therapy but a number of key challenges have limited translation of inhaled CF gene medicines to-date including: i) inadequate gene delivery efficiency ii) inadequate screening tools for nanomedicines iii) inefficient aerosol delivery. Our team harnesses pharmacoengineering approaches to overcome each of these challenges by integrating advances in our understanding of CF disease with cutting edge materials science, particle engineering, medical device design and tissue-engineering tools to support the development and clinical translation of RNAi-nanomedicines. We have developed a series of star polypeptide-based gene vectors in RCSI3,4. They are built from amino acids and are thus bio-derived, biodegradable and biocompatible by definition. One of the main barriers to gene delivery in the CF patient is the thick barrier mucous that coats the epithelium. We have now tailored these star-polypeptides specifically for delivery to and into respiratory tissues by decorating the surface of the stars with mucouspenetrating polymers.

In the first stages of the PhD project the student will use these novel materials to prepare miRNAnanomedicines that will be characterized for their mucous-penetrating and pharmaceutical properties. A key roadblock to-date in the development of CF gene therapies has been the lack of valid tools for translation to comprehensively screen new vector systems. To overcome this barrier and to reduce dependence on in vivo models we have developed high content imaging approaches for screening nanomaterials5 and an innovative 3D collagen-hyaluronic acid bilayered construct that enables culturing of primary human cells in an extracellular matrix (ECM) environment to better recapitulate the human airway6. The RNAinanomedicines will be screened using these state-of-the-art in vitro models with lead miRNA-nanomedicines being assessed using the 3D model seeded with primary CF cells. Finally, key to the clinical use of inhalable gene therapies is integration with an appropriate inhaler device. The student will work with industrial collaborators to integrate the miRNA-polypeptide nanomedicines into devices for aerosol testing to create a drug-device combination suitable for clinical translation.

The student will be supported by an experienced, multidisciplinary team on a project focused on the emerging field of pharmacoengineering, at the interface of pharmaceutical sciences and biomedical engineering, and will have an opportunity to work with the team’s extensive network of clinical and industrial collaborators.

References

1. Oglesby IK, et al. Eur Respir J 2015;46(5):1350-60.
2. McKiernan, P.J., et al. (2013) International Journal of Nanomedicine, 8, pp. 3907-3915.
3. Byrne, M. et al. (2013) Biomaterials Science, 1 (12), pp. 1223-1234
4. Walsh DP, et al., Mol Pharm. 2018 May 7;15(5):1878-1891.
5. Brayden, D.J., et al., (2015) Drug Discovery Today, 20 (8), art. no. 1607, pp. 942-957.
6. O'Leary C, et al., Biomaterials. 2016 Apr;85:111-27.

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