New Mouse Model

The Lilly and Blair Foundation is proud to fully fund the creation of a new mouse model for SPG4. This project is a critical part of our research strategy – providing scientists with a powerful tool to unravel the disease and accelerate the search for a cure. Below, we outline what this project entails and why it’s so important. We invite you to read more and consider supporting this and our other research efforts.

Overview: To treat SPG4, we first have to understand it — and to understand it, researchers need a model that mirrors what’s happening in children. Until now, that hasn’t existed. Most current models either overexpress mutant genes on top of normal ones or knock genes out entirely. Neither approach reflects the true genetic profile of kids living with de novo SPG4.
Thanks to donor support, The Lilly and Blair Foundation has fully funded the creation of a first-of-its-kind humanized mouse model for SPG4 that changes that. Dr. Peter Baas of Drexel University and Cyagen are developing a knock-in mouse model in which:

  • The mouse’s native spastin (Spast) gene is completely removed

  • It is replaced by two human SPAST alleles

  • One is a wild-type (normal) copy

  • The other carries the severe Arg499His mutation — a common and aggressive variant found in many children with SPG4

This results in a genotype of SPAST+/Arg499His, mimicking the real human disease with unprecedented accuracy. It will allow researchers to observe the disease from its earliest stages, test life-changing therapies, and answer questions we’ve never been able to ask before.

This mouse model is the foundation for everything that comes next. Without it, there’s no way to move promising therapies forward. With it, we can finally test whether gene therapy or other treatments can stop — or even reverse — the progression of SPG4.

Scientific and Strategic Rationale: SPG4 is caused by mutations in the SPAST gene, which encodes spastin — a critical protein involved in maintaining healthy microtubules in neurons. Microtubules are essential for transporting nutrients and signals throughout nerve cells. When spastin is deficient or dysfunctional, axons begin to degenerate, particularly in the longest neurons of the corticospinal tract.
Our mouse model allows researchers to:

  • Track microtubule stability over time

  • Identify early biomarkers of axon degeneration

  • Understand when symptoms begin and which systems are affected first

  • Investigate whether motor neurons, sensory neurons, or other cell types are most vulnerable

This model is also tightly aligned with our broader research roadmap. It will directly support:

  • Preclinical validation of our AAV9-SPAST gene therapy project

  • Future evaluation of other delivery systems, such as lipid nanoparticles or dual vectors

  • Collaboration with industry and academic partners seeking to advance SPG4-specific compounds

Because the model is based on a human genetic background, it offers far greater translational value than older models — increasing the chances that discoveries made in the lab will succeed in human trials.

Timeline: The project was initiated in 2024 and mouse model completion is expected in summer 2025, with therapeutic testing to begin late 2025 and beyond.

Advantages of a New Mouse Model

  • Test Therapeutics


    Evaluate AAV9-based gene therapy designed to deliver a healthy copy of SPAST

    Test antisense oligonucleotides (ASOs) to silence mutant transcripts or modulate splicing

    Investigate small-molecule drugs like HDAC6 inhibitors or microtubule stabilizers

    Explore combination therapies and determine if certain agents are synergistic

  • Optimize Treatment Delivery


    Determine dosage, route, and frequency for each treatment candidate

    Identify optimal therapeutic windows for early or late intervention

    Monitor off-target effects or toxicity across tissues

  • Study Disease Mechanisms


    Analyze axon degeneration, mitochondrial transport, and neuronal morphology

    Understand why some kids experience cognitive decline, speech loss, or progression to the arms and core

    Uncover the timeline of symptom emergence — helping families and clinicians predict what comes next

Research Team

  • Peter Baas, PhD

    Professor; Director, Graduate Program in Neuroscience, Department of Neurobiology and Anatomy, Drexel University College of Medicine

Together We Can

Time is not on our side, but we hope you will be.