About the Project
NEC is a severe neonatal condition that commonly affects premature neonates with significant morbidity and mortality (up to 50% in patients requiring surgery, with limited improvement in the last 30 years). The pathogenesis is not completely understood, but it is known to be associated with poor intestinal perfusion, bacterial translocation and progressive inflammation ultimately leading to necrosis and/or intestinal perforation1,2. Presently there are no effective treatments for NEC. The economic cost of NEC accounts for ~ 19% of neonatal expenditures and an estimated $5-6 billion per year for hospitalizations in the United States. Thus, NEC has major implications for the patient, their family and society as a whole3.
The UCL team together with Micregen (non-academic partner) have shown that the secretome produced by amniotic fluid stem cells (AFSC) alter key cell activities in mouse model of NEC leading to greatly improved tissue structure and function2,4,5. As a step towards translation towards clinical use, Micregen have developed a novel AFSC therapeutic (development name MRG1061) which can be produced at scale to GLP/GMP standards. This has demonstrated an ability to attenuate disease severity in the mouse NEC model. Micregen have held two scientific advice meetings with the Medicines and Healthcare products Regulatory Agency (MHRA) with the aim of developing a Phase I/II clinical trial in partnership with UCL. One of the key recommendations from the MHRA was the need for a portfolio of evidence for efficacy and dosing a secondary rodent model of NEC (namely the rat model).
This project will generate key data, essential for developing a clinical trial for NEC by determining the effectiveness and optimal dosing, route of administration as well as formulation of MRG1061 in treating rat model of NEC.
The aims of the project are:
- Establish the rat model of NEC (Home Office project licence granted)
- Compare the intraperitoneal, intravenous, and oral route of MRG1061 administration
- Established the optimal volume of dose of MRG1061 as treatment for rat NEC
- Develop molecular and cellular evidence for MRG1061 mode of action as treatment for NEC and NEC related diseases in the neonate
- Write a portfolio for the MHRA.
This project will equip a promising and talented candidate in interdisciplinary quantitative, scientific, medical and business skills that will enable them to advance care provided to patients through clinical translation of a novel therapeutic. Successful clinical translation and regulatory approval of MRG1061 should reduce long-term disability and morbidity associated with NEC.
Furthermore, this project will train a candidate to also develop deep understanding of entrepreneurship, medicine and health economics that will help develop a new breed of clinician-scientist with an entrepreneurial and commercial mindset that can drive future business growth.
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References
1. Li, B., Lee, C., O’Connell, J., Antounians, L., Ganji, N., & Alganabi, M. et al. (2020). Activation of Wnt signaling by amniotic fluid stem cell-derived extracellular vesicles attenuates intestinal injury in experimental necrotizing enterocolitis. Cell Death &Amp; Disease, 11(9). doi: 10.1038/s41419-020-02964-22.
2. Zani, A., Cananzi, M., Fascetti-Leon, F., Lauriti, G., Smith, V., & Bollini, S. et al. (2013). Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism. Gut, 63(2), 300-309. doi: 10.1136/gutjnl-2012-303735
3. Bisquera, J., Cooper, T., & Berseth, C. (2002). Impact of Necrotizing Enterocolitis on Length of Stay and Hospital Charges in Very Low Birth Weight Infants. Pediatrics, 109(3), 423-428. doi: 10.1542/peds.109.3.423
4. O'Connell JS, Li B, Zito A, Ahmed A, Cadete M, Ganji N, Lau E, Alganabi M, Farhat N, Lee C, Eaton S, Mitchell R, Ray S, De Coppi P, Patel K, Pierro A. Treatment of necrotizing enterocolitis by conditioned medium derived from human amniotic fluid stem cells. PLoS One. 2021 Dec 2;16(12):e0260522. doi: 10.1371/journal.pone.0260522.
5. Mellows B, Mitchell R, Antonioli M, Kretz O, Chambers D, Zeuner MT, Denecke B, Musante L, Ramachandra DL, Debacq-Chainiaux F, Holthofer H, Joch B, Ray S, Widera D, David AL, Huber TB, Dengjel J, De Coppi P, Patel K. Protein and Molecular Characterization of a Clinically Compliant Amniotic Fluid Stem Cell-Derived Extracellular Vesicle Fraction Capable of Accelerating Muscle Regeneration Through Enhancement of Angiogenesis. Stem Cells Dev. 2017 Sep 15;26(18):1316-1333. doi: 10.1089/scd.2017.0089
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