Pioneering platform-based approaches to turn the promise of gene therapy into tangible cures for rare diseases
Imagine a world where a single genetic error no longer dictates a lifetime of suffering. For the millions of people affected by rare diseases, this vision is inching closer to reality, thanks to groundbreaking work in gene therapy.
At the heart of this revolution is an unusual institute at the National Institutes of Health (NIH) – the National Center for Advancing Translational Sciences (NCATS). Unlike other institutes that focus on specific organs or diseases, NCATS acts as a master engineer for the entire medical research process, systematically dismantling the roadblocks that slow down the development of treatments for everyone. Nowhere is this mission more critical than in the realm of rare genetic diseases, where NCATS is pioneering innovative, platform-based approaches to turn the promise of gene therapy into tangible cures.
Established in 2011, NCATS was founded on a radical idea: to treat translation itself as a science3 . Instead of focusing on individual diseases, NCATS studies what is common across all diseases—the scientific and operational principles that underlie every step of the journey from a laboratory observation to a treatment that helps a patient3 .
This mission is vital when confronting the staggering challenge of rare diseases. There are more than 10,000 known rare diseases, but only a few hundred have safe, effective treatments7 . About 80% of these conditions are caused by a mutation in a single gene2 , making them ideal candidates for gene therapy. Yet, because each individual rare disease affects a small number of people, they often lack commercial interest, leaving patients and their families with few options2 .
NCATS tackles this problem by developing "platform" approaches—standardized methods that can be adapted for many different diseases quickly and efficiently3 . Gene therapy, with its ability to target the root cause of thousands of monogenic disorders, is the ultimate platform technology, and a perfect fit for the NCATS playbook.
Standardized methods that can be adapted for many different diseases quickly and efficiently.
NCATS studies the common principles underlying the journey from laboratory observation to patient treatment.
NCATS doesn't work alone. Its power lies in collaboration and team science, bringing together experts from across NIH, industry, patient advocacy groups, and regulatory agencies3 . Through a suite of strategic programs, NCATS is building a new, more efficient pathway for gene therapies.
This NCATS-led pilot project tests the feasibility of using the same gene delivery system (AAV9 viral vector) and manufacturing methods for four different rare diseases5 .
As part of this NIH Common Fund program, NCATS helps create high-quality tools for safe and effective genome editing to decrease the time and cost of creating new therapies2 .
Identification of genetic cause and therapeutic approach
Testing in laboratory models and optimization of delivery system
Production of clinical-grade vectors under strict regulations
Phase 1/2/3 studies to evaluate safety and efficacy in patients
FDA review and approval for clinical use
The story of the MMA-101 clinical trial perfectly illustrates the unique role NCATS plays in the research ecosystem. Methylmalonic acidemia (MMA) is a rare, often life-threatening metabolic disorder. Patients cannot properly break down certain proteins and fats, leading to a toxic buildup of substances in the blood and organs, which can cause kidney disease, intellectual disabilities, and frequent life-threatening metabolic crises1 .
For years, researcher Dr. Charles Venditti at the National Human Genome Research Institute (NHGRI) collaborated with a biotech company, Selecta Biosciences, to develop a gene therapy for a form of MMA. They carried out successful preclinical studies, showed benefit in mouse models, and even received FDA approval to begin testing in people1 . Then, in 2023, just weeks before the first patient was to be treated, the company halted the project for financial reasons. For the MMA community, it was a devastating blow.
The MMA-101 trial is more than just a potential treatment for a single disease; it's a model for how to run future gene therapy trials at NIH.
This collaborative, NIH-wide effort ensures that the momentum behind this promising therapy was not lost, giving new hope to the MMA community and laying the operational groundwork for many more trials to come1 .
Developing a gene therapy like MMA-101 requires a sophisticated array of tools and reagents. The table below details some of the essential components used by researchers in this field.
| Tool/Reagent | Function | Example Use in Gene Therapy |
|---|---|---|
| Viral Vectors (e.g., AAV, Lentivirus) | Acts as a delivery vehicle to transport therapeutic genes into human cells. | The AAV8 vector is used in the MMA-101 trial to deliver a healthy MMUT gene to liver cells1 . |
| DNA Polymerases (e.g., KOD One™) | Enzymes that amplify DNA sequences with high speed and fidelity during preclinical research4 . | Used to generate high-quality DNA constructs for creating the viral vector itself. |
| Peptide Pools (e.g., PepMix™) | Overlapping peptides representing a whole protein, used to monitor immune responses in patients8 . | Critical for assessing immunogenicity—checking if a patient's immune system is reacting negatively to the viral vector capsid or a tool like CRISPR-Cas98 . |
| qPCR & RT-qPCR Reagents | Used to precisely quantify gene expression levels and monitor the presence of the therapeutic gene4 . | Researchers use these to measure how successfully the new gene has been delivered and is functioning in target cells. |
| Cell Transfection Reagents | Chemicals or materials that introduce DNA, RNA, or proteins into eukaryotic cells in the lab4 . | Essential for early-stage in vitro experiments to test gene function before moving to animal models or human trials. |
Therapeutic Gene
Viral Vector
Target Cell
Therapeutic Effect
"We're not only addressing an urgent need for the MMA community, but also building a framework that could accelerate future rare disease trials at NIH."
The work spearheaded by NCATS is pointing toward a future where gene therapy is not an exotic, prohibitively expensive last resort, but a more standardized and accessible treatment modality.
"Democratize the use of gene therapy by lowering costs, increasing accessibility, and hopefully reducing barriers for commercialization."
By treating the development process itself as a scientific problem to be solved, NCATS is ensuring that the revolutionary potential of gene therapy can one day reach every patient who needs it.
Reusable templates for gene therapy development that can be rapidly adapted for different rare diseases, significantly reducing development time and costs.
More affordable and available gene therapies for patients with rare diseases, regardless of commercial interest or prevalence of their condition.