Research

The Lilly and Blair Foundation is not just funding research; we are architecting a cure. To move from the laboratory to a human clinical trial, we drive a coordinated attack across three strategic pillars:

Therapeutic Development: We are engineering the "medicine" itself, utilizing gene editing, ASOs, and drug repurposing to fix the genetic root of SPG4.
Modeling and Testing Platforms: We build the living laboratories—from humanized mice to 3D organoids—required to prove these medicines are safe and effective.
Clinical Trial Readiness: We are building the regulatory bridge, establishing the blood tests and natural history data the FDA requires to approve a cure.

Therapeutic Development

AAV9 Gene Therapy

Rewriting the genetic code to stop SPG4 at its source.

Background: SPG4 results from mutations in the SPAST gene, leading to a "toxic gain-of-function" where mutant spastin protein damages motor neurons and a "loss-of-function" where there isn’t enough healthy protein to maintain nerve infrastructure.
Strategy: We use an AAV9 viral vector to deliver a healthy SPAST gene directly into the central nervous system to "Silence and Replace", shutting down the mutant gene while turning on a healthy version.
Solution: While this worked in mouse models, transitioning to larger rat models showed that spastin levels must be perfectly balanced—too much can be toxic. We are now testing a final set of AAV9 vectors with moderate promoters and high concentrations to hit that precise therapeutic window.
Impact: A successful one-time AAV9 treatment could halt disease progression and protect motor neurons from further degeneration.
ASOs and the Humanized Mouse Model

A precision "dimmer switch" to neutralize toxic SPG4 proteins.
Background: Mutant spastin protein accumulates and causes nerve damage. If we stop the body from ever building that toxic protein, we can save the nerves.
Strategy: Antisense Oligonucleotides (ASOs) are synthetic genetic strands designed to find "toxic instructions" (mutant RNA) and destroy them before they are translated into harmful protein.
Solution: ASOs must match human DNA exactly, so they cannot be tested in standard lab mice. The Humanized R499H Mouse Model, fully funded by The Lilly and Blair Foundation, carries the exact human genetic sequence, providing the only platform in the world to validate these "clinic-ready" ASOs.
Impact: ASOs offer a highly tunable, reversible therapy that can be adjusted or stopped if needed, providing a flexible safety path for children with severe mutations.
Drug Repurposing

Finding new hope in existing, FDA-approved medications.
Background: Developing a brand-new drug takes 10–15 years. Children with SPG4 need relief now. Many existing medications may have "hidden" benefits that can stabilize microtubules.
Strategy: Our team uses high-throughput screening on human cells to identify existing drugs that can "unclog" the transport system in nerves and restore cellular health.
Solution: We are currently focusing on HDAC6 Inhibitors and other microtubule-stabilizing agents. These drugs are already safety-tested for other conditions, meaning they can move into SPG4 clinical trials much faster.
Impact: This approach identifies safe, existing medications that can be moved into the clinic almost immediately to improve quality of life while we finalize genetic cures.
Combinatorial and Supportive Therapies

A "cocktail" approach to maximize recovery and nerve health.

Background: Simply fixing the gene may not be enough to restore mobility if nerves are already damaged. We must both stop the damage and repair the existing system.
Strategy: We believe the final cure could be a "cocktail" combining genetic fixes with supportive therapies that help the nervous system "re-wire" itself.
Solution: Drexel University College of Medicine is researching M1 Antibodies to "mop up" existing toxic proteins, alongside Neurostimulation to encourage nerves to "re-sprout." Our team is also tracking small molecules like AKV9 for their potential to protect nerve endings.
Impact: This ensures we aren't just stopping the disease, but actively helping children regain lost function and strength.
Gene and Prime Editing

Precision "molecular editors" to fix the mutation within the patient’s own DNA.

Background: Traditional gene therapy adds a new gene, but the cell may struggle to regulate its output. This can lead to the "overexpression" lethality observed in some rat models.
Strategy: Instead of adding a new gene, our team is considering utilizing Prime Editing machinery delivered via AAV to act as a molecular "find and replace" tool.
Solution: The team would develop editors that target and correct the mutation directly within the child's original DNA. This allows the cell’s natural sensors to regulate spastin levels automatically, bypassing the "Goldilocks" dosage requirement.
Impact: This represents a permanent, self-regulating correction that restores the patient's genetic code to its healthy state.

Modeling and Testing Platforms

The Humanized R499H Mouse Model

The world’s first living roadmap for the most severe SPG4 mutation.

Background: To test modern genetic medicines like ASOs or Gene Editors, the laboratory model must carry the exact human genetic sequence. Standard mice do not have the human SPAST gene, making them "invisible" to these precision drugs.
Strategy: We invested in the creation of a "humanized" model—a mouse engineered to carry the human SPAST gene with the severe R499H mutation found in many children.
Solution: Fully funded by the Lilly and Blair Foundation, this model is now the global "gold standard" for testing. It allows us to validate "clinic-ready" therapies in a living system that mimics human biology.
Impact: This model removes the guesswork from drug development, providing the high-level safety and effectiveness data required to gain FDA clearance for human trials.
Large Animal Science: SPG4 Cattle

Bridging the gap from lab mice to human reality.
Background: A mouse’s spinal cord is only a few centimeters long. A human child’s nervous system is vastly larger and more complex. Dosing and delivery methods that work in a tiny mouse often fail to scale up to a human.
Strategy: We maintain a dedicated herd of SPG4-affected cattle at Hillcrest Farm. Because their size and spinal cord complexity are closer to a human’s, they serve as a vital "natural model."
Solution: By studying how therapies travel through the nervous system of these large animals, we can refine our delivery techniques (such as IV or spinal injections) to ensure the medicine reaches the target nerves in a human child.
Impact: The insights gained from Hillcrest Farm ensure that we have the right "map" and the right dosage before we move into the clinic, significantly increasing the chances of trial success.
3D Brain Organoids

Creating a living laboratory from a patient’s own cells.
Background: To find the right treatment, we need to see how human neurons behave. Standard cell cultures don't capture the complex "wiring" of the human brain.
Strategy: The Qiang Lab (Drexel), has grown 3D Brain Organoids (mini-brains) from the stem cells of children with the R499H mutation.
Solution: These organoids have the exact DNA of some of our children, serving as the "engine" for drug repurposing screens and providing a human environment to test gene therapies.
Impact: This platform allows us to see how human nerves react to treatments in real-time, providing proof-of-concept for every therapy in our pipeline.

Clinical Trial Readiness

The NULISA Study: Biomarker Discovery

Establishing the blood test that will unlock FDA approval.

Background: The FDA will not approve a drug unless we can prove it is working through "biomarkers"—measurable indicators in the blood. Historically, no such marker has existed for SPG4.
Strategy: Fully funded by The Lilly and Blair Foundation, Boston Children’s Hospital is utilizing the ultra-sensitive NULISAseq platform to scan for a unique "protein fingerprint" in the blood of SPG4 patients.
Solution: BCH is analyzing longitudinal samples to identify specific proteins that change as the disease progresses. This will create a scalable blood test to monitor treatment response.
Impact: A validated biomarker allows for shorter, more efficient clinical trials. Instead of waiting years to see if a child's walking improves, we can see if the therapy is working in weeks via a simple blood test.
The Natural History Studies: SP-CERN and Pediatric Tracking

Building the definitive roadmap for SPG4 across a lifetime.
Background: To cure a disease, you must first define it. Without a clear understanding of how SPG4 progresses from the first sign of symptoms through adulthood, regulators like the FDA cannot determine if a new treatment is truly effective.
Strategy: We support the global registry and longitudinal study led by Dr. Darius Ebrahimi-Fakhari at Boston Children’s Hospital (NCT04712812). This network connects researchers worldwide to track the lived experience of SPG4 patients of all ages.
Solution: SP-CERN collects standardized clinical assessments, advanced gait analysis, and bio-samples over many years. This creates a "Master Database" that defines the disease's trajectory and identifies the specific windows of time where treatments will be most impactful.
Impact: This work transforms SPG4 from a "rare unknown" into a "trial-ready" disease. It provides the essential "baseline" data that scientists, clinicians, and regulatory bodies need to design, validate, and approve the clinical trials of tomorrow.

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The SPG4 Biobank: Coriell Institute

Providing the biological "building blocks" for global research.
Background: Researchers cannot study SPG4 without access to patient cells. A centralized biobank ensures that scientists everywhere have the samples they need to innovate.
Strategy: We encourage families to contribute blood or skin samples to the NIGMS Repository at the Coriell Institute, an international biobank.
Solution: These samples are the foundation of our work; for example, the 3D Brain Organoids grown at Drexel were created using samples from this very biobank.
Impact: By donating a sample, families provide the raw materials for a thousand different experiments, ensuring that SPG4 research never hits a "supply chain" bottleneck.
Learn more and contribute a sample »
HSPseq: Genomic Sequencing Initiative

Unlocking the full genetic spectrum of childhood spasticity.
Background: Not every child with spasticity has a clear answer. Defining the full genomic landscape of HSP is essential for personalized medicine and early diagnosis.
Strategy: Led by Boston Children’s Hospital, the HSPseq study combines clinical data with advanced genomic sequencing for patients aged 1 month to 30 years.
Solution: This initiative identifies new genes and better defines the spectrum of SPG4, helping families get answers sooner—regardless of whether they have a known or unknown genetic diagnosis.
Impact: Earlier diagnosis means earlier intervention. HSPseq ensures that as new therapies come online, every child is correctly identified and ready to receive treatment.

Learn more and enroll »