Unlocking a new frontier in drug discovery: Rethinking disease mechanisms through the lens of transcription factor biology
But here’s where it gets intriguing—most complex diseases are not driven by a single molecular culprit. Instead, they involve intricate networks and multiple factors. Scripta Therapeutics is pioneering a transformative approach by examining how transcription factors—the primary controllers of gene activity—shape disease signatures, opening new pathways for identifying disease drivers.
Traditionally, drug development has been centered around a target-based paradigm. Scientists would pick a protein believed to be involved in a disease, create a molecule to modulate its activity, and then see if this results in clinical improvement. While this has led to many effective medicines, its shortcomings have become ever more evident, especially in tackling complex, multi-layered conditions like neurodegenerative disorders. Many late-stage clinical failures are now understood to stem from an incomplete grasp of disease biology and an overdependence on targets that are well-studied but not necessarily the most relevant.
Simultaneously, breakthroughs in genomics and transcriptomics—the science of measuring gene activity on a large scale—have revolutionized how scientists analyze biological systems. Instead of zooming in on single proteins, researchers can now observe how thousands of genes change their expression patterns in disease, helping to rebuild the networks of gene regulation that underpin pathology.
Central to these regulatory networks are transcription factors—proteins that directly bind to DNA to switch genes on or off. Fluctuations in their activity are often responsible for the gene expression changes characteristic of disease states. By mapping the networks governed by these factors, we can reveal the complex biological circuitry underlying multifaceted diseases, including neurodegeneration.
Thanks to advancements in technologies—like multiomics (integrating genomics, transcriptomics, proteomics), sophisticated cellular models, high-content imaging, and Artificial Intelligence (AI)—we can now directly measure transcription factor activity at the level of individual cells and in large quantities. Moreover, evidence from clinical and genetic studies shows that pathways involving transcription factors can be indirectly adjusted by targeting upstream regulators, reinforcing their potential as therapeutic targets. This has revitalized interest in drugs aimed at transcription factor pathways.
Founded in 2025, Scripta Therapeutics is dedicated to applying this innovative approach specifically to neurodegenerative diseases like Alzheimer’s, aiming to uncover novel treatments.
From a platform perspective, founder and CEO Peter Hamley brings over 20 years of experience in big pharma and biotech. His career launched at AstraZeneca in the UK, followed by a leadership role at Sanofi, overseeing global chemistry teams supporting multiple drug discovery projects. Later, he shifted focus to business development, fostering partnerships with biotech innovators such as Schrödinger, PeptiDream, X-Chem, and Exscientia. His role as Chief Scientific Officer at Samsara Therapeutics, a start-up tackling neurodegeneration, further deepened his understanding of biologically driven failures in drug development.
Having participated in numerous projects, Hamley realized a critical insight: many failures in drug development are not due to poor chemistry or execution but are rooted in flawed biological hypotheses. As he points out, most target selection stems from biased scientific literature—often reflecting trends, funding priorities, or historical focus—leading to the repetitive pursuit of the same targets, while potentially more relevant biological drivers are ignored. This bias hampers progress, and a more comprehensive, unbiased approach that truly reflects human biology could accelerate success.
Why do transcription factors matter so much? These proteins—about 1,600 encoded in our genome—are master regulators, directing gene programs that influence cell identity, adaptation, and function. When these programs go awry—as seen in many diseases—they produce specific transcriptional signatures indicative of underlying pathology.
Modern multiomic technology allows scientists to profile these signatures directly in patient tissues and disease models. Computational tools then help deduce which transcription factors are orchestrating the observed changes, turning complex data into actionable insights. Each transcription factor controls a unique set of genes, which can be analyzed using advanced transcriptomic methods.
Over recent years, improvements in computational biology and large data set analysis have made it possible to reconstruct gene regulatory networks with greater accuracy. These tools help distinguish cause from effect—identifying upstream regulators responsible for disease processes—an essential step in understanding neurodegenerative disorders, where multiple pathways and cell types intertwine.
At Scripta, discovery starts from disease-specific gene signatures rather than predefined molecular targets. The company studies transcription factor activity within cellular contexts to identify upstream disease drivers, then leverages proprietary biological networks to pinpoint druggable regulatory nodes.
To make this possible, Scripta employs multiplexed live-cell imaging—an innovative way to observe transcription factor activity in real-time within living cells. Advanced AI and computer vision techniques analyze this data, enabling simultaneous assessment of multiple transcription factors and early discrimination of potential selective modulators.
Another cornerstone of their approach is integrating patient-derived data. By combining post-mortem tissue analyses with models derived from induced pluripotent stem cells (iPSCs), Scripta recreates disease-relevant cell types—such as neurons, astrocytes, and microglia—to understand disease processes more accurately. This layered data approach allows mapping how transcription factor networks change across different disease stages, genetic backgrounds, and cell populations. It provides not only a roadmap for target identification but also insights into how potential therapies may act.
One of the toughest challenges is that transcription factors are often considered 'undruggable'—mainly because they lack obvious binding pockets for small molecules and act through protein–protein or protein–DNA interactions, which are hard to disrupt directly. Scripta’s strategy is to target the regulatory pathways that control these transcription factors indirectly. By modulating upstream proteins that influence their stability, localization, or activation, they can effectively adjust transcription factor activity.
This approach isn’t purely theoretical. For example, drugs like Skyclarys (omaveloxolone) activate the Nrf2 pathway by inhibiting KEAP1, without binding Nrf2 directly, yet they effectively modify disease-relevant gene programs. Such success stories validate the potential of targeting transcription factor pathways indirectly.
Why start with Alzheimer’s disease? The answer lies in both unmet needs and scientific opportunity. Despite decades of intense research, Alzheimer’s remains poorly understood at a comprehensive systems level, and effective disease-modifying treatments are still lacking. Hamley believes that an unbiased, holistic approach—such as the one Scripta employs—can uncover novel insights into disease mechanisms.
Early work using patient-derived models has already identified known transcription factors involved in Alzheimer’s, plus others less studied but potentially crucial. These discoveries open doors to truly novel biological pathways, offering hope for new therapeutic strategies.
Scripta is committed to a 'lab in the loop' model—rapidly connecting biology, screening, and validation by continuously learning from each experiment. This approach refines target discovery and helps advance promising molecules toward clinical testing.
In early 2025, Scripta secured $12 million in seed funding, led by Oxford Science Enterprises and Apollo Health Ventures. Over the next 1.5 to 2 years, the company plans to expand its platform capabilities, conduct large-scale cellular screens, and enhance AI and bioinformatics systems to accelerate the journey from discovery to clinical application for Alzheimer’s and other neurodegenerative diseases.
While initially focused on neurological disorders, the company’s platform also holds promise for other illnesses driven by transcriptional dysregulation—including immune-related conditions, cardiovascular diseases, and even aging. Their core philosophy questions: Could targeting the regulatory blueprints of cell function revolutionize treatment for a multitude of complex diseases? And what if the key drivers we’re missing aren’t proteins themselves, but the networks controlling them? Share your thoughts—do you agree that transcription factor biology is the future of drug discovery, or do you believe this approach overlooks critical challenges? Let’s start the conversation.
