For much of modern medical history, treating disease has revolved around drugs: chemical compounds that remove unwanted invaders or rebalance the body’s dysfunctions. However, advances in molecular biology are driving a new wave of medicine that harnesses a more fundamental level of life—the workings of cells and genes themselves—to achieve those ends.
“Cell- and gene-based therapies (CGT) represent the next frontier of medicine,” said Xinyi Su, Executive Director of the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB). “As opposed to traditional small molecule or antibody-based therapeutics, CGT has long-lasting effects, offering the potential of curing disease as opposed to simply controlling it.”
CGT innovations are rooted in exploiting fundamental biological mechanisms. These include the blueprint-like nature of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) molecules, directing protein building and cell behaviour; as well as the ways cells respond and adapt to certain cues. By engineering nucleic acids, genes and whole cells to repair their defects, enhance their functions or grant them new abilities, researchers aim to equip the body against ever-evolving disease conditions.
“A*STAR has recognized the potential and strategic importance of building CGT capabilities and continues to play a pivotal role in advancing CGT research in Singapore through leadership in national platforms and initiatives,” said Sze Wee Tan, Assistant Chief Executive of A*STAR’s Biomedical Research Council (BMRC).
Working with life’s messages
Gene therapies can take many forms, from molecular tools that cut and replace damaged sections of DNA to transient messengers that help cells make new proteins. Building on decades of discoveries about the code of life, researchers at the A*STAR Genome Institute of Singapore (A*STAR GIS) and A*STAR IMCB are exploring how these tools might treat otherwise intractable conditions.
“In general, gene therapies are highly adaptable because they’re based on easily-modified molecular sequences,” said Yue Wan, A*STAR GIS Executive Director. “This allows us to quickly and effectively make new products that meet different patient needs or tackle evolving variants of disease-causing agents.”
Messenger RNA (mRNA) is a particular platform of interest for Wan and colleagues. Previously an obscure area of molecular medicine, RNA-based interventions came into the public spotlight during the COVID-19 pandemic, which saw the development of vaccines that used mRNA sequences to train immune systems against SARS-CoV-2 infection.
Wan added that mRNA therapies are relatively safe as their molecules degrade rapidly and are not incorporated into the DNA genome. However, this instead poses the challenge of shorter lifespans and a need for repeated doses.
To push the frontiers of this emerging technology, scientists like Leslie Beh are figuring out how to design more stable and long-lived synthetic mRNA molecules. An A*STAR IMCB Principal Investigator, Beh leads a team focusing on modifications to optimise mRNA’s biomedical functions.
“It remains poorly understood how the number, type and location of RNA modifications affect mRNA properties: not just their stability, but the protein products they translate to, and the immune reactions they trigger,” said Beh. “A deeper understanding of the biochemistry involved could pave the way for RNA-based therapies with better clinical benefits.”
Beh’s team is developing enzymatic methods to modify synthetic mRNA with high efficiency and precision. Through these techniques, they hope to carefully craft modifications that improve the stability of mRNA therapeutic platforms and mitigate their immunogenicity, enabling molecular therapies to turn the tide against devastating diseases.
Wan added that A*STAR GIS is collaborating with fellow institutes such as the A*STAR Bioprocessing Technology Institute (A*STAR BTI) to package mRNA with lipid nanoparticles for efficient delivery to target tissues. They are also developing artificial intelligence (AI) for foundational RNA modelling and therapeutic design in partnership with the A*STAR Institute of High Performance Computing (A*STAR IHPC) and A*STAR Institute for Infocomm Research (A*STAR I2R).
“Under the leadership of Jay Shin, who heads our Regulatory Genomics group, A*STAR GIS is also working with the A*STAR Advanced Remanufacturing and Technology Centre (A*STAR ARTC) and A*STAR Singapore Institute of Manufacturing Technology (A*STAR SIMTech) to automate processes for generating standardised omics data, which will be used to train AI models for RNA expression and stability,” said Wan.
Cutting at viral blueprints
Gene editing technologies such as the Nobel Prize-winning CRISPR-Cas9 have opened new doors for molecular biologists, enabling them to snip at genomes with surgical precision. Wei Leong Chew, A*STAR GIS Associate Director for Genome Design, hopes to transform these innovative tools into safe and effective medical agents.
Chew’s group is currently devising novel DNA and RNA editors that tackle challenging viruses. One such target is EV-A17, the enterovirus behind hand, foot and mouth disease (HFMD), which primarily afflicts children with painful mouth ulcers, stinging limb blisters and high fevers. As there is still no clinically-approved drug to treat EV-A17, Chew and colleagues looked to gene editing therapy for potential solutions.
With Cas13gRNAtor, an in-house bioinformatics pipeline, the team designed guide RNAs (gRNAs) that could be attached to CRISPR-Cas13 molecules, aiming their gene-snipping abilities at EV-A17 viral RNA. Using an adeno-associated virus (AAV) as a delivery vehicle, they tested out their novel CRISPR-Cas13-gRNA molecules on human cells as well as mice models lethally infected with EV-A17.
“Our AAV-CRISPR-Cas13 therapy shredded EV-A17’s RNA genome and its mRNAs into pieces, which safely and effectively destroyed the virus within infected cells,” said Chew. “We showed that the technology can both prevent future infections and treat ongoing infections; remarkably, it even prevented the death of the lethally-infected mice.”
Such potent effects against HFMD ignite the hope that these gene therapies could be further developed against other viruses including SARS-CoV-2, influenza and future Disease X agents. To amplify the impact of their work, the team is now developing broad-spectrum antivirals through a project supported by the National Programme for Research in Epidemic Preparedness and Response (PREPARE).
Arming cells against cancers
Where some medical interventions pose safety issues due to an over-reactive immune system, cancer cells take advantage of an under-reactive one. Tumours often find themselves in—or create—immunosuppressive microenvironments, allowing them to evade death and continue to cause harm. However, recent clinical successes in cancer immunotherapy have shown how one’s immune system can be empowered to detect and eliminate these stealthy opponents, enlisting the combative prowess of T cells—the body’s frontline fighters against disease.
Typically, cancer cells express unique proteins that slip under the immune system’s radar. Now, researchers are training T cells to recognise these markers, allowing them to target tumours with pinpoint precision. Advances in cellular engineering are even enabling other immune cells, such as natural killer (NK) cells, to be outfitted with persistent, T cell-like tumour-killing capabilities.
Such T cell-mediated immunity can be further bolstered by a bit of creative engineering, as Qi-Jing Li believes. As A*STAR IMCB’s Chief Innovation Officer, Li is breaking new ground with his team in designing ‘armoured’ immune cell therapies against solid cancers.
Besides attacking tumours directly, these enhanced T cells also release factors that help cultivate an immunocompetent environment, much like having tiny pharmacies delivered right to the cancer site. Beyond enhancing the treatment’s effects, Li also hopes that the armoured forms remain active and maintain an anti-tumour memory over longer periods.
“While tumours present an unfamiliar and hostile battlefield for our immune system, there’s a growing consensus that combination therapies are essential to overcoming the complex challenges they pose,” said Li. “T cells and NK cells offer a versatile platform on which we can integrate a range of anti-cancer weaponry.”
With promising early results from multiple clinical trials, it’s all hands on deck for Li’s team as they integrate clinical findings with benchwork. Through comprehensive immune monitoring of human patients, the team hopes to gain new insights into the diversity of immune cell profiles and the mechanisms that form persistent anti-tumour memory, sparking new ideas to help patients with treatment-resistant disease.
Towards healthier cell fates
The well-controlled secretion of molecules is not only critical to activate the body’s immunological warriors, but to keep the body in overall balance. Take blood sugar: when sugar levels rise, special cells in the pancreas, called beta cells, secrete insulin in response, triggering a series of biological pathways that remove glucose from the blood and store it in cells for later energy needs. However, in patients with diabetes, these regulatory mechanisms are impaired either due to a reduced response to insulin or its insufficient production.
While much existing research on diabetes and pancreatic function has used rodent models, researchers led by A*STAR IMCB Senior Principal Investigator and Division Director Adrian Kee Keong Teo are turning to human induced pluripotent stem cells (iPSCs) for more accurate insights and exciting therapeutic prospects.
A class of unspecialised cells, iPSCs can be coaxed to mature into various cell types, granting researchers the flexibility to examine how cells change at a molecular level as they develop. They are also potential materials for cell replacement therapy, where the loss of function from impaired cells—such as beta cells in diabetes—might be compensated for by healthier counterparts.
“We’ve performed various studies with human iPSCs in recent years to conscientiously map the role of human transcription factors, genes and proteins in human pancreatic beta cells,” said Teo, who directs A*STAR IMCB’s Cell and Molecular Therapy Division.
The team has mapped an East Asian-specific genetic variation in the PAX4 gene which adds to diabetes risk by decreasing insulin production and hampering insulin secretion. “Based on such mechanistic findings, we’re also working to identify receptors that make good druggable targets for restoring pancreatic beta cell function,” Teo added.
Early clinical trials elsewhere have shown that human iPSC-derived pancreatic beta cells, when transplanted into patients with diabetes, can release insulin as needed to maintain healthy blood sugar levels, bypassing the need for regular insulin injections.
“If approved by regulatory bodies, this may be the first application of human iPSC-derived cells to fulfil the promise of cell replacement therapy,” Teo commented. “To advance this field, we’re collaborating with A*STAR IMCB spinoff BetaLife for translational iPSC-derived beta cell research, and we are also applying for funding to generate Asian iPSCs that comply with Current Good Manufacturing Practice (CGMP) standards.”
Bringing cells to scale
Like other emerging therapeutics, CGT innovations can be challenging to roll out to clinics. Biological products like cells typically require distinct environments to remain viable, such as subzero temperatures for long-term preservation, or special surface coatings to facilitate their growth outside the body.
“Beyond simply shipping cell-based therapies ‘fresh’ at ambient or chilled temperatures, it’s essential to extend their shelf life, as well as ensure their proper storage, processing and transportation in appropriate packaging,” said Senior Scientist Alan Lam, who heads the A*STAR Bioprocessing Technology Institute (A*STAR BTI)’s Stem Cell Bioprocessing Group.
The group aims to resolve these logistical bottlenecks, starting by accelerating iPSC production. With their recently-developed Reprogramming on Microcarriers (RepMC) platform, stem cells are plated onto tiny custom-made beads which offer a precisely constructed environment: one that not only stimulates stem cell specialisation into a desired cell type, but also allows the selection of high-quality stem cell clones.
“RepMC is well-suited for automating iPSC generation as it processes more samples than other culturing methods, yet has a compact design,” Lam added.
Through active collaborations with A*STAR BTI’s Biomanufacturing Technology Group and Bioprocess Data Integration Group, Lam and colleagues are harnessing robotics and AI to develop a fully automated system for a complete iPSC production workflow. In partnership with A*STAR IMCB and clinical biotech company SCG Cell Therapy, they also aim to accelerate the translation of iPSC technologies from labs to scalable cGMP-compliant manufacturing processes.
“Our primary goal is to establish robust, reliable and reproducible methods to generate clinical-grade iPSCs and their differentiated therapeutic products, which can be turned into cost-effective cell therapies for a range of conditions,” said Lam.
Adoption on the horizon
The dream of customised, off-the-shelf CGT solutions is one that resonates across the whole sector, as many A*STAR experts interviewed for this piece agree. Despite their promising clinical efficacy, however, advances in CGT are still hampered by the costs of production.
“Without addressing the issue of affordability, widespread clinical adoption of CGT will be challenging,” said Xinyi Su.
To tackle these barriers, A*STAR’s BMRC is spearheading an institutional-level programme known as CGT Flagship, which aims to improve patient access to CGT by upscaling production, and to carve opportunities for CGT’s effective use in an increasing array of Asian-centric conditions.
“CGT Flagship plays a critical role in seeding projects and platforms that will strengthen our CGT research capabilities and strategically position A*STAR researchers toward addressing technical hurdles in this industry,” explained Sze Wee Tan.
The programme also serves to coordinate the diverse CGT research endeavours at A*STAR, further fostering collaborations and synergies within the CGT community. With the shared goal of realising impact-driven healthcare innovations, the Flagship goes hand-in-hand with several other initiatives in the broader Singapore CGT ecosystem (see inset).
“Beyond research funding and internal coordination, CGT Flagship will increase our synergy with other ecosystem efforts to facilitate, pull through and foster a collaborative CGT community that sparks impactful innovations,” concluded Tan.
At a glance: CGT ecosystem collaborations
Nucleic Acid Therapeutics Initiative (NATi): Hosted by A*STAR, NATi aims to position Singapore as a regional hub for NAT research, clinical translation and commercialisation. The NATi mRNA BioFoundry was launched at A*STAR BTI in November 2024 to rapidly scale up production of mRNA-based products, especially during national health emergencies.
Singapore Cell Therapy Advanced Manufacturing Programme (STAMP): Established in 2019, STAMP 1.0 united 11 public research agencies with local and international biotech industry players to address bottlenecks in cell therapy manufacturing by expanding product portfolios and supporting clinical development of biotech assets. STAMP 2.0 will establish a national integrated cell therapy programme to develop novel manufacturing technologies for multiple cell therapies.
Process Accelerator for Cell Therapy Manufacturing (PACTMAN): A joint lab between A*STAR and the Advanced Cell Therapy Research Institute, Singapore (ACTRIS) to develop clinical trial materials, PACTMAN serves as a testbed for optimising novel cell therapy assets and production processes.
iPSCs-differentiated Natural Killer cells for cancer immunotherapies (PANAKEIA): Drawing resources from A*STAR, SingHealth and the National University of Singapore, PANAKEIA aims to develop a next-generation production platform for off-the-shelf iPSC-based NK cells, and to generate advanced NK cell-based cancer treatments.
Circular RNA (circRNA) vaccines: A research collaboration between A*STAR and Hilleman Laboratories to develop and validate a circRNA vaccine for Nipah virus. Tapping into circRNA’s rapid adaptability and superior stability versus linear RNA, the team aims to broaden its applications for infectious diseases, particularly in developing countries.
