New research published in Science Advances explored a potential novel treatment approach incorporating Thrombospondin-1 mimetic protein-like polymers (TSP1 PLPs) to manage neovascular age-related macular degeneration (nAMD).
I need some background on this.
We’ll start with the fact that the use of intraocular anti-vascular endothelial growth factor (anti-VEGF) injections, a common treatment for AMD, can be ineffective in up to one-third of nAMD patients.
Thus, there is an unmet need for a treatment that targets patients with anti-VEGF-resistent nAMD.
Explain TSP-1.
TSP-1 is an extracellular matrix protein that interacts with cell surface receptors like CD36 (a transmembrane protein key in angiogenesis regulation) and is known for inhibiting angiogenesis.
In nAMD, abnormal angiogenesis causes proliferation of new blood vessels which could lead to vision loss.
To note, prior research has found that TSP-1 levels reduce with age as well as even further in the late stages of AMD, suggesting that the protein is protective in nAMD pathogenesis, according to the study authors.
This brings us to the research in question: Investigators sought to better understand the mechanism of TSP-1, a potential natural anti-angiogenic agent, for nAMD.
I’m listening.
The researchers developed TSP1 PLPs—nano-sized, synthetic compounds engineered to mimic the behavior of natural proteins (like TSP1) with the intention to target specific cellular processes.
These PLPs then bind with CD36 (remember: this is a protein key in angiogenesis) to interfere with the formation of abnormal blood vessels associated with nAMD.
How were these tested?
Ex vivo and in vivo mouse models were compared against prior studies evaluating both rabbits and humans. The following analyses were performed:
- Assessment of TSP1 PLP’s anti-angiogenic properties via ex vivo choroidal sprouting assay
- Assessment of cytotoxicity of TSP1-PLPs in vitro of adult RPE cells
- Assessment of TSPI PLP toxicity in vivo of health mice
- Assessment of TSP1 PLP for protease resistance vs peptide alone via enzyme resistance assay
- Comparison of TSP1 PLP binding to ABT898 thrombospondin peptide via biolayer interferometry (BLI)
- Assessment of CD36 binding via cell-based in vitro fatty acid inhibition assay
See here for details on all testing, including detailed findings.
Now the results.
Overall, TSP1 PLPs were found to:
- Bind CD36 with a high affinity
- Resist degradation
- Exhibit prolonged intraocular half-lives (13.1 hours)
- Compared to aflibercept, bevacizumab, and ranibizumab
- Contain no toxicity at relevant concentrations in vivo (400 μM)
- Be more efficacious in ex vivo choroidal sprouting vs peptide sequence and Eylea (aflibercept) combined
What else?
Independently, PLPs exhibited “superior in vivo efficacy in a mouse model for nAMD compared to control PLPs consisting of scrambled peptide sequence,” according to the study.
Meaning ….
Due to TSP1 PLP’s ability to inhibit angiogenesis via both VEGF-dependent and independent mechanisms, “TSP1 PLPs are potential therapeutic targets for patients with anti-VEGF treatment-resistant nAMD,” the authors concluded.
What else?
The authors stated that additional studies will be needed to determine if low doses of TSP1 PLP have additive and/or synergistic effects when used with anti-VEGF agents.