Researchers have proposed a new exosome-based strategy to suppress the formation of blood vessels in the eye, bringing new hopes of treating neovascular diseases.
In the eye, a healthy, intact retina is key to maintain clear vision. But new blood vessels can grow beneath the retina in an area called the choroid. When these newly-formed blood vessels leak or bleed in the retina, they can lead to vision loss. This condition is known as choroidal neovascularisation and is most often caused by age-related macular degeneration and other diseases that stress the retina, including diabetic retinopathy.
At present, treatments for this degenerative eye condition and other ocular neovascular diseases often involve the use of therapeutic agents that prevent the growth of new blood vessels. In particular, injecting antibodies that target the vascular endothelial growth factor (VEGF) into the eye to block the activity of VEGF and suppress pathogenic angiogenesis has become a well-established practice. However, this form of therapy is riddled with challenges including fast metabolism with the aqueous humour, poor accumulation in lesions, and limited efficacy. Moreover, many patients still demonstrate an incomplete response to this VEGF antibody treatment.
To improve present treatment methods, researchers from the Institute of Process Engineering of the Chinese Academy of Sciences, Beijing Chaoyang Hospital, and the University of Queensland have developed a new therapeutic formulation based on regulatory T-cell exosomes to deliver VEGF antibodies for choroidal neovascularisation therapy.
In their study, the team first collected samples of aqueous humour samples derived from patients and quantified their VEGF levels as well as other proinflammatory cytokines. According to Professor Tao Yong from Beijing Chaoyang Hospital, they “observed a strong association between inflammation and high VEGF expression in aqueous humour samples.” Given these observations, the team sought to develop a synergistic therapeutic approach that combines both anti-VEGF and anti-inflammatory therapies. They were also interested in finding a better way to deliver the VEGF antibodies into targeted lesions, specifically by exploring better carriers of therapeutic agents.
Of the various bio-vesicles commonly used to carry therapeutics, the team chose to focus their study on exosomes that were isolated from regulatory T-cells. They conjugated these vesicles with the VEGF antibodies using a peptide linker that can be cleaved by matrix metalloproteinases in inflammatory lesions. Upon testing the efficacy of their new formulation, it was revealed that the combination of exosomes from the regulatory T-cells, peptide linker, and VEGF antibody (rEXS-cL-aV) could significantly suppress ocular neovascularisation in mouse and non-human primate models of choroidal neovascularisation.
Professor Wei Wei from the Institute of Process Engineering explained how their technology works, "This design concept could achieve efficient spatiotemporal delivery for combination therapy. After intravitreal injection, rEXS-cL-aV exploited the ability of rEXS to localize in neovascularization lesions and, upon MMP-mediated cleavage, released rEXS and aV to suppress inflammation and VEGF activity, respectively."
Besides its anti-angiogenic and anti-inflammatory effects, the new exosome-based treatment also boasts versatility. The engineered exosomes, which selectively accumulate in neovascularisation lesions, have been found to be adaptable for other combination therapies of therapeutic antibodies and anti-inflammatory cargo. Therefore, experts believe that it can become a promising tool to advance treatments for not only neovascular diseases but also many others that may stand to benefit from exosome therapy.
Currently, while no exosome products have received approval from the U.S. Food and Drug Administration, the study’s novel findings are expected to help validate the benefits of bringing exosome therapy into clinical practice. As said by Professor Yu Di from the University of Queensland, “Given that [regulatory T-cell exosomes] can be produced from the patients' own cells and [VEGF antibody] has been approved for clinical use, our rEXS-cL-aV has the potential for translation to clinic."
Source: Tian et al. (2021). Reduction of choroidal neovascularization via cleavable VEGF antibodies conjugated to exosomes derived from regulatory T cells. Nature Biomedical Engineering.