Gene therapy holds immense promise for treating a wide array of genetic disorders, but one of its biggest challenges remains the delivery of therapeutic materials to target cells. Current delivery vectors, such as lentivirus, adenovirus, adeno-associated virus (AAV), and lipid nanoparticles (LNPs), each come with limitations. Some randomly integrate into the genome, leading to unintended consequences; others trigger immune responses or exhibit low efficiency. The biomedical community is continuously striving to overcome these hurdles, and a groundbreaking innovation may be the key to advancing the field further.
On August 19, 2021, Feng Zhang’s team introduced a novel solution to gene therapy delivery challenges with their study, published in Science. The study described the development of SEND (Selective Endogenous eNcapsidation for cellular Delivery), an innovative RNA delivery platform centered on PEG10, a retrovirus-like protein capable of encapsulating its own mRNA and forming virus-like particles. This breakthrough demonstrates the potential for safer, more effective RNA delivery, offering new avenues for gene therapy.
The Core of SEND: PEG10
The SEND system leverages the retroviral-like protein PEG10, naturally found in humans. PEG10 originates from retrotransposons, ancient virus-like genetic elements that integrated into human ancestors’ genomes millions of years ago. Over time, these elements were repurposed by the body for crucial biological functions, with PEG10 becoming part of the human protein pool.
Zhang’s team discovered that PEG10 can bind its own mRNA and encapsulate it within a protective vesicle, mimicking a virus’s ability to transport genetic material. This unique property of PEG10 makes it ideal for RNA delivery. By modifying PEG10, the team adapted it for encapsulating and transporting therapeutic RNA, including tools like the CRISPR-Cas9 system, to human and mouse cells. Successful delivery and editing of target genes using SEND marked a significant milestone, demonstrating the system’s potential as a novel delivery platform for gene therapy.
Engineering PEG10 for Precision Delivery
To harness PEG10’s delivery capabilities, Zhang’s team carried out a series of meticulous modifications. They first identified sequences within PEG10’s mRNA responsible for recognizing and packaging RNA. By editing both the PEG10 protein and its mRNA sequence, they enhanced PEG10’s ability to selectively package therapeutic RNA molecules.
Further, the researchers fused PEG10 with proteins that promote efficient fusion with cell membranes, enabling better delivery of RNA into target cells. These modifications not only optimized RNA encapsulation but also paved the way for targeted delivery to specific cells, tissues, or organs, a critical advancement in gene therapy precision.
Advantages of the SEND System
The SEND platform offers several advantages over traditional gene delivery methods:
- Safety: Unlike viral vectors, which may integrate into the genome and cause off-target effects, SEND relies on naturally occurring human proteins. This reduces the risk of triggering unintended immune responses.
- Reusability: SEND’s protein-based delivery system could potentially be reused for multiple therapeutic applications with minimal risk of immune-related side effects.
- Customizability: By engineering PEG10, the platform can be tailored for specific RNA cargo and targeted delivery, enhancing its applicability to diverse therapeutic needs.
- Compatibility with Existing Technologies: Feng Zhang emphasized that SEND could complement existing delivery tools, such as viral vectors and lipid nanoparticles, expanding the toolbox for gene therapy and enabling the delivery of complex therapeutic molecules.
Inspired by Retrotransposons
The inspiration for SEND originated from the discovery of other retrotransposon-derived proteins with similar properties. In 2018, Jason Shepherd’s lab identified the ARC protein, another retrotransposon-derived molecule capable of forming virus-like structures and facilitating RNA transfer. While ARC demonstrated the feasibility of using retrotransposons for RNA delivery, it had not yet been employed successfully in mammalian cells for therapeutic RNA packaging.
Building on this foundation, Zhang’s team conducted a systematic search of the human genome, identifying 48 genes encoding retroviral-like proteins with potential delivery capabilities. Among these, PEG10 stood out as the most promising candidate due to its ability to naturally release RNA-encapsulating particles in both mice and humans.
SEND: A Promising Future for Gene Therapy
SEND represents a transformative leap in gene therapy. Its reliance on naturally occurring proteins minimizes immune activation, addressing one of the most significant challenges faced by current delivery vectors. Additionally, its adaptability for precision targeting opens the door to treating previously inaccessible tissues and organs.
While further research is needed to confirm SEND’s safety and efficacy in clinical settings, early results suggest it could become a cornerstone of next-generation gene therapy. By complementing existing tools like viral vectors and lipid nanoparticles, SEND has the potential to expand therapeutic options and reduce treatment-associated risks.
As the field of molecular medicine continues to evolve, the development of platforms like SEND highlights the importance of innovative delivery systems. These advancements not only enhance the efficacy of gene editing and RNA therapies but also bring the promise of safer, more accessible treatments closer to reality.
In the words of Feng Zhang, “SEND technology could complement existing delivery systems and expand the toolbox for delivering genes to cells and gene-editing therapies.” With ongoing research and optimization, SEND is poised to redefine the landscape of gene therapy, offering hope to millions of patients worldwide.
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