BioE COLLOQUIA SERIES: "Design of siRNA-Loaded Lipidoid-Polymer Hybrid Nanoparticles for Local RNAi-Based Treatment of Chronic Obstructive Pulmonary Disease (COPD)"
Event details
| Date | 04.11.2019 |
| Hour | 12:15 |
| Speaker | Prof. Camilla Foged, University of Copenhagen (DK) |
| Location | |
| Category | Conferences - Seminars |
WEEKLY BIOENGINEERING COLLOQUIA SERIES
(sandwiches served)
Abstract:
Therapeutics based on RNA interference (RNAi) are highly target-specific and promising for the treatment of serious diseases lacking definite clinical management, e.g. chronic obstructive pulmonary disease (COPD), characterized by persistent airflow limitation and chronic airway inflammation, progressively leading to loss of airway function. The cytokine tumor necrosis factor (TNF)-α released by macrophages is associated with active inflammation during COPD. Currently, no single, definitive therapy exists against COPD. However, targeting cytokines via the RNA interference (RNAi) pathway is one approach for management of the early inflammatory phase in COPD. RNAi is mediated by small interfering RNA (siRNA), which is capable of inducing selective and highly potent gene silencing. However, intracellular delivery of siRNA to the RNAi pathway in the cytosol remains a challenge. The efficacy of siRNA therapeutics is fully dependent on technologies that safely can facilitate intracellular delivery. We have made a major breakthrough by inventing a delivery technology based on well-tolerated lipidoid-polymer hybrid nanoparticles (LPNs) with an unprecedented ability to deliver siRNA to target tissues (1,2). This technology is ten times more efficient than state-of-the-art delivery systems and thus allows for dose reduction, which improves the safety profile and reduces cost of goods. We are using LPNs to silence key genes involved in COPD. We have proof-of-concept in vivo that LPNs loaded with siRNA against TNF-α can reduce experimental inflammation. This presentation focusses on how we solve fundamental scientific and technical preclinical challenges necessary for the further design and progression of the siRNA-loaded LPNs from the preclinical stage towards clinical testing. In particular, I will focus on (i) how we have applied a quality-by-design-based approach for the design and optimization of TNF-α siRNA-loaded LPNs for local RNAi-based treatment of COPD, and (ii) how to scale up the manufacture of powder-based dosage forms with properties suitable for inhalation (3). In addition, I will present data providing a mechanistic profiling of the release kinetics of siRNA from LPNs in vitro and in vivo after pulmonary administration (4). This knowledge contributes significantly to increasing our understanding of the basic requirements for controlling and sustaining the delivery of the siRNA cargo to lung tissue for local management of disease.
References:
1. Thanki K, Zeng X, Justesen S, Tejlmann S, Falkenberg E, Van Driessche E, Nielsen HM, Franzyk H, Foged C. Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach. Eur J Pharm Biopharm. 2017;120:22-33.
2. de Groot AM, Thanki K, Gangloff M, Falkenberg E, Zeng X, van Bijnen DCJ, van Eden W, Franzyk H, Nielsen HM, Broere F, Gay NJ, Foged C, Sijts AJAM. Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design. Mol Ther - Nucleic Acids. 2018;11:159-169.
3. Dormenval C, Lokras A, Cano-Garcia G, Wadhwa A, Thanki K, Rose F, Thakur A, Franzyk H, Foged C. Identification of Factors of Importance for Spray Drying of Small Interfering RNA-Loaded Lipidoid-Polymer Hybrid Nanoparticles for Inhalation. Pharm Res. 2019;36(10):142.
4. Thanki K, van ED, Geyer A, Fraire J, Hendrix R, Van EH, Putteman E, Sami H, de SC-W, Franzyk H, Nielsen HM, Braeckmans K, Lehr CM, Ogris M, Foged C. Mechanistic profiling of the release kinetics of siRNA from lipidoid-polymer hybrid nanoparticles in vitro and in vivo after pulmonary administration. J Control Release. 2019;310:82-93.
Bio:
Camilla Foged is Full Professor of Vaccine Design and Delivery at the Department of Pharmacy at University of Copenhagen (since 2018), Denmark. Her main research area is advanced drug delivery, in particular design of new vaccine and nucleic acid delivery systems to improve therapy. Drug delivery challenges are addressed using state-of-the-art technologies, and this has fostered innovative solutions and high-impact publications in drug delivery. Her research goal is to improve disease prevention and treatment in the fields of infectious and inflammatory diseases and cancer. These aims are approached by imaging-guided design of nanoparticle-based vaccine and nucleic acid formulations, and she engages in research projects spanning from early discovery phase projects to first-in-man clinical studies. She is widely recognized nationally and internationally in the field of drug delivery, and she has a well-established and extensive network of national and international collaborators in academia and industry. Her research has been funded with more than EUR 8 million via prestigious and highly competitive grants. She has an MSc in Biochemistry from University of Copenhagen (1998), and she attained her PhD in Pharmaceutics in 2003 from The Danish University of Pharmaceutical Sciences. Prof. Foged has edited one book about subunit vaccine delivery, and she has (co)authored more than 110 scientific papers/book chapters and 175 conference abstracts at national and international conferences.
Zoom link for attending remotely: https://epfl.zoom.us/j/461567156
(sandwiches served)
Abstract:
Therapeutics based on RNA interference (RNAi) are highly target-specific and promising for the treatment of serious diseases lacking definite clinical management, e.g. chronic obstructive pulmonary disease (COPD), characterized by persistent airflow limitation and chronic airway inflammation, progressively leading to loss of airway function. The cytokine tumor necrosis factor (TNF)-α released by macrophages is associated with active inflammation during COPD. Currently, no single, definitive therapy exists against COPD. However, targeting cytokines via the RNA interference (RNAi) pathway is one approach for management of the early inflammatory phase in COPD. RNAi is mediated by small interfering RNA (siRNA), which is capable of inducing selective and highly potent gene silencing. However, intracellular delivery of siRNA to the RNAi pathway in the cytosol remains a challenge. The efficacy of siRNA therapeutics is fully dependent on technologies that safely can facilitate intracellular delivery. We have made a major breakthrough by inventing a delivery technology based on well-tolerated lipidoid-polymer hybrid nanoparticles (LPNs) with an unprecedented ability to deliver siRNA to target tissues (1,2). This technology is ten times more efficient than state-of-the-art delivery systems and thus allows for dose reduction, which improves the safety profile and reduces cost of goods. We are using LPNs to silence key genes involved in COPD. We have proof-of-concept in vivo that LPNs loaded with siRNA against TNF-α can reduce experimental inflammation. This presentation focusses on how we solve fundamental scientific and technical preclinical challenges necessary for the further design and progression of the siRNA-loaded LPNs from the preclinical stage towards clinical testing. In particular, I will focus on (i) how we have applied a quality-by-design-based approach for the design and optimization of TNF-α siRNA-loaded LPNs for local RNAi-based treatment of COPD, and (ii) how to scale up the manufacture of powder-based dosage forms with properties suitable for inhalation (3). In addition, I will present data providing a mechanistic profiling of the release kinetics of siRNA from LPNs in vitro and in vivo after pulmonary administration (4). This knowledge contributes significantly to increasing our understanding of the basic requirements for controlling and sustaining the delivery of the siRNA cargo to lung tissue for local management of disease.
References:
1. Thanki K, Zeng X, Justesen S, Tejlmann S, Falkenberg E, Van Driessche E, Nielsen HM, Franzyk H, Foged C. Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach. Eur J Pharm Biopharm. 2017;120:22-33.
2. de Groot AM, Thanki K, Gangloff M, Falkenberg E, Zeng X, van Bijnen DCJ, van Eden W, Franzyk H, Nielsen HM, Broere F, Gay NJ, Foged C, Sijts AJAM. Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design. Mol Ther - Nucleic Acids. 2018;11:159-169.
3. Dormenval C, Lokras A, Cano-Garcia G, Wadhwa A, Thanki K, Rose F, Thakur A, Franzyk H, Foged C. Identification of Factors of Importance for Spray Drying of Small Interfering RNA-Loaded Lipidoid-Polymer Hybrid Nanoparticles for Inhalation. Pharm Res. 2019;36(10):142.
4. Thanki K, van ED, Geyer A, Fraire J, Hendrix R, Van EH, Putteman E, Sami H, de SC-W, Franzyk H, Nielsen HM, Braeckmans K, Lehr CM, Ogris M, Foged C. Mechanistic profiling of the release kinetics of siRNA from lipidoid-polymer hybrid nanoparticles in vitro and in vivo after pulmonary administration. J Control Release. 2019;310:82-93.
Bio:
Camilla Foged is Full Professor of Vaccine Design and Delivery at the Department of Pharmacy at University of Copenhagen (since 2018), Denmark. Her main research area is advanced drug delivery, in particular design of new vaccine and nucleic acid delivery systems to improve therapy. Drug delivery challenges are addressed using state-of-the-art technologies, and this has fostered innovative solutions and high-impact publications in drug delivery. Her research goal is to improve disease prevention and treatment in the fields of infectious and inflammatory diseases and cancer. These aims are approached by imaging-guided design of nanoparticle-based vaccine and nucleic acid formulations, and she engages in research projects spanning from early discovery phase projects to first-in-man clinical studies. She is widely recognized nationally and internationally in the field of drug delivery, and she has a well-established and extensive network of national and international collaborators in academia and industry. Her research has been funded with more than EUR 8 million via prestigious and highly competitive grants. She has an MSc in Biochemistry from University of Copenhagen (1998), and she attained her PhD in Pharmaceutics in 2003 from The Danish University of Pharmaceutical Sciences. Prof. Foged has edited one book about subunit vaccine delivery, and she has (co)authored more than 110 scientific papers/book chapters and 175 conference abstracts at national and international conferences.
Zoom link for attending remotely: https://epfl.zoom.us/j/461567156
Practical information
- Informed public
- Free
Organizer
- Prof. Li Tang, EPFL
Contact
- Institute of Bioengineering (IBI), Christina Mattsson