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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Local anti-angiogenic therapy by magnet-assisted downregulation of SHP2 phosphatase
Sarah Rieck1, Yvonn Heun2, Alexandra Heidsieck3
1Institute of Physiology I, Life & Brain Center, Medical Faculty, University of Bonn, Germany.
Abstract:
Anti-angiogenic therapies are promising options for diseases with enhanced vessel formation such as tumors or retinopathies. In most cases, a site-specific local effect on vessel growth is required, while the current focus on systemic distribution of angiogenesis inhibitors may cause severe unwanted side-effects. Therefore, in the current study we have developed an approach for the local inhibition of vascularization, using complexes of lentivirus and magnetic nanoparticles in combination with magnetic fields. Using this strategy in the murine embryonic stem cell (ESC) system, we were able to site-specifically downregulate the protein tyrosine phosphatase SHP2 by RNAi technology in areas with active vessel formation. This resulted in a reduction of vessel development, as shown by reduced vascular tube length, branching points and vascular loops. The anti-angiogenic effect could also be recapitulated in the dorsal skinfold chamber of mice in vivo. Here, site-specific downregulation of SHP2 reduced re-vascularization after wound induction. Thus, we have developed a magnet-assisted, RNAi-based strategy for the efficient local inhibition of angiogenesis in ESCs in vitro and also in vivo.
Insights
Researchers developed a new magnet-assisted RNAi method to locally inhibit blood vessel growth. This targeted approach reduces unwanted side effects associated with systemic anti-angiogenic therapies for conditions like tumors.
Area of Science:
- Biotechnology
- Molecular Biology
- Regenerative Medicine
Background:
- Anti-angiogenic therapies are crucial for diseases with abnormal blood vessel formation, such as tumors and retinopathies.
- Current systemic treatments for angiogenesis inhibition can lead to severe side effects due to widespread distribution.
- There is a need for localized strategies to control vessel growth precisely where needed.
Purpose of the Study:
- To develop a novel, site-specific method for inhibiting angiogenesis.
- To utilize magnetic nanoparticles and lentivirus complexes for targeted delivery of RNA interference (RNAi).
- To investigate the downregulation of SHP2 (a protein tyrosine phosphatase) as a mechanism for local anti-angiogenesis.
Main Methods:
- Employing lentivirus and magnetic nanoparticle complexes guided by magnetic fields for targeted delivery.
- Utilizing RNAi technology to specifically downregulate SHP2 in murine embryonic stem cells (ESCs).
- Assessing anti-angiogenic effects in vitro using ESCs and in vivo using a mouse dorsal skinfold chamber model.
Main Results:
- Successful site-specific downregulation of SHP2 in areas of active vessel formation in ESCs.
- Demonstrated reduction in vascular tube length, branching, and vascular loops, indicating inhibited angiogenesis.
- Validated the local anti-angiogenic effect in vivo, showing reduced re-vascularization after wound induction in mice.
Conclusions:
- A magnet-assisted, RNAi-based strategy effectively achieves local inhibition of angiogenesis.
- This approach allows for precise control over vascularization in both in vitro (ESCs) and in vivo (mouse models) settings.
- The developed method offers a promising alternative to systemic anti-angiogenic therapies, minimizing potential side effects.
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