果冻传媒

For a long time, scientists thought that our immune system is innate and that memory picked up while battling pathogens is stored in memory cells like memory T cells. However, increasing evidence points towards our body鈥檚 innate immune system鈥檚 ability for trained immunity. 

Nanomedicine can work with this innate mechanism to create therapies for immune diseases. Schrijver studied long-lasting innate immune memory in bone marrow-residing stem cells, developed nano-immunotherapy strategies targeting the innate immune system and established a nanoparticle platform to treat sepsis induced immunoparalysis.

Best of both worlds

This research combines unique insights from both engineering and clinical developments. 鈥淎s an immunologist, I had a very steep learning curve transferring from an academic hospital to the world of engineering at the 果冻传媒鈥�, explains David Schrijver. 

The collaboration with Radboudumc, specifically the group of prof. dr. Mihai Netea, was crucial to bring together fundamental understanding of molecular biology and clinical perspectives. 

Schrijver: 鈥淭he 果冻传媒 is a great institution to develop and engineer new nanotechnology. However, to test these using primary human cells and mouse models it essential to team up with the immunologists and clinicians from the Radboudumc.鈥� Schrijver also collaborated with scientists and doctors from Amsterdam University Medical Centers and the Icahn School of Medicine at Mount Sinai New York.

Nanoparticle platform for genetic therapies

During his research at the Precision Medicine group Schrijver established nanoparticle platforms containing apoA1 (the main protein component of high-densitiy lipoporitein cholesterol)-cytokine-fusion proteins to treat sepsis induced immunoparalysis. 

Immunoparalysis is a complication that often occurs in people with serious infections. Due to the persistent inflammation, the immune system is paralyzed, so that no immune response is initiated anymore. The result is that patients often die from a secondary infection such as pneumonia.

Developing the nanoparticle platform was no easy task. Schrijver: 鈥淐ytokines are notoriously difficult proteins to express recombinantly.鈥� The combination with the intrinsic properties of apoA1 to interact with lipids, including the lipids present in our bacterial expression systems made it hard to obtain 鈥榩ure and clean鈥� proteins to create nanoparticle formulations to use in medicines. 

鈥淗owever,鈥� Schrijver says, 鈥渨e managed to develop a protocol in which we completely unfold the protein, subsequentially wash it, and refold back to the original active structure retaining its therapeutic effect.

Promising new therapeutic strategies

Schrijver also worked on antigen-fusion proteins as vaccination strategy for the treatment of cancer and infectious diseases. Herein, the apoA1 -fusion protein platform was adapted to harbour an antigen fused to apoA1 and adjuvants in the core over the nanoparticle. This new vaccination platform promises to become a versatile new technology that can be used in a broad range of disease including but not limited to cancer, sepsis and ulcerative colitis.

Finally, in an explorative journey to find new targets to treat inflammatory bowel disease, Schrijver discovered, using high dimensional profiling techniques, that during ulcerative colitis progression, the bone marrow activates and potentially contributes to colitis progression. These finding provide new opportunities for therapeutic interventions using nanoparticle technology. 

Next steps: Princess M谩xima Center for Paediatric Oncology 

Schrijver always had an interest in developing therapeutic strategies. During his studies 
Biomedical Science and Biomolecular Science, he performed internships at various institutions including VUMC, Sanquin and the Cancer Centre Amsterdam (CCA). Schrijver: 鈥淗ere, I became inspired by the diversity and power of the immune system, its strict regulation and severe consequences when it spirals out of control.鈥� 

He acknowledges the importance of better understanding the molecular biology that underlies immune system related diseases but is most interested in how this knowledge can be utilized to develop therapeutic strategies to treat disease.

After his PhD Schrijver has started a post-doc position at the Princess M谩xima Center for Paediatric Oncology where he works on therapeutic strategies to treat paediatric brain tumours.

Title of PhD Thesis: Bioengineered Therapeutic Strategies to Rebalance the Immune System.

Supervisors: Willem Mulder and Maarten Merkx