Gene Therapy Project for SPG4

The Lilly and Blair Foundation is proud to co-fund the Gene Therapy Project for SPG4 – an unprecedented, multi-institutional effort to develop a cure for SPG4 and advance it to clinical trials within the few years. Below you’ll find an overview of the project and its goals. We invite you to donate and support this critical work on the path to a clinical trial.

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Project Overview

Introduction

This ambitious gene therapy project is a collaborative initiative uniting four leading research centers – Boston Children’s Hospital, Drexel University College of Medicine, UMass Chan Medical Center, and the University of Wisconsin–Madison. Our shared goal is to develop a gene therapy for SPG4, originally based on an AAV9 vector (delivered via ICV), with a projected timeline of approximately two years to first-in-human clinical trial. As of May 2025, the project is evolving to support a new delivery strategy using the PHP.eB capsid by IV injection, which may accelerate the path to trial. The total project budget remains substantial (nearly $3 million), but the potential impact is extraordinary: if successful, this therapy would be applicable to all individuals with SPG4, regardless of their specific SPAST mutation. In other words, a single treatment emerging from this research could transform thousands of lives now and in the future.

Project Status

May 2025 Update: Shift to PHP.eB Capsid and IV Delivery

Our team has transitioned to using the PHP.eB capsid, enabling intravenous (IV) gene therapy delivery in place of the original AAV9 intracerebroventricular (ICV) approach. As the project evolves, a new TFRC rat model is being used to test this updated delivery strategy. This shift offers several scientific and clinical advantages:

Vector change: PHP.eB allows for systemic IV delivery, eliminating the need for brain surgery while improving central nervous system (CNS) targeting and safety for trial participants.
Animal model update: Cow and pig models are currently on hold. Instead, the team is validating the TFRC rat model as the primary efficacy model. This study is already underway and expected to conclude by August 2025.
Because PHP.eB is not compatible with large animal models, the team anticipates no FDA requirement for large animal studies, significantly reducing preclinical complexity and cost. Aims 1–3 remain fully funded and underway. With the capsid switch and the potential removal of large animal studies, the overall cost structure is evolving—and total funding needs may ultimately be lower. Fundraising continues for future aims, pending revised timelines following rat model validation.
Next steps: Once the rat model study is complete and the vector is validated, a revised project timeline and updated budget will be finalized.

Essential Study Aims

In July 2024, The Lilly and Blair Foundation provided funding for the first three aims of this gene therapy project for SPG4. These initial aims—set to be completed by summer 2025—will generate the foundational data needed to support a Pre-IND meeting for a Phase I/II clinical trial.

Aims 1–3 remain fully funded and in progress under the current PHP.eB capsid strategy.
Aims 4–7 are being actively reevaluated based on outcomes from the ongoing TFRC rat model study.

Aim 1: Testing AAV9-SPAST Vectors in Patient Cells

Cost: $43,600
Aim 2: Therapeutic Effect in a Rat Model of SPG4

Cost $142,875
Aim 3: Prepare for Clinical Trials

Cost: $82,992

Detailed Project Aims

Note: The aims below reflect the current structure of the project under the PHP.eB IV-delivery approach.

Aims 1–3: Fully funded and underway
Aims 4–7: On hold pending results from the TFRC rat study and updated regulatory guidance

This section outlines the purpose and status of each aim, noting where adjustments may occur as the project evolves.

Status: Active – Funded and in progress
Purpose: Evaluate the ability of AAV vectors to deliver and express normal SPAST genes in cells derived from SPG4 patients.
Experimental Design: Patient-derived cells will be exposed to therapeutic vectors to assess gene delivery efficiency and restoration of spastin function.
Timeline: Approximately 6 months
Status: Active – Funded and in progress (now using TFRC rat model)
Purpose: Assess the therapeutic potential of gene therapy in improving motor function and neurological symptoms in a rat model of SPG4.
Experimental Design: A TFRC rat model deficient in spastin is being used to test the PHP.eB-SPAST vector. Motor function and disease progression will be monitored to evaluate therapeutic efficacy.
Timeline: Study underway; expected to conclude by August 2025
Outcome: Provide key preclinical data to guide regulatory and clinical planning
Status: Active – Funded and ongoing
Purpose: Collect essential preclinical data and establish protocols necessary for future clinical trials.
Study Design: Document disease progression in SPG4 patients, establish a biobank for research samples, and develop a comprehensive clinical trial protocol.
Timeline: Ongoing, with milestones including 12-month longitudinal data collection
Objective: Lay groundwork for transitioning from preclinical research to clinical application
Status: On hold pending vector and model validation
Purpose: Evaluate efficacy of gene therapy in correcting spastin deficiency in patient-derived neurons.
Note: Timeline and design may be revised pending results from TFRC rat study and PHP.eB vector validation.
Status: On hold pending vector and model validation
Purpose: Investigate therapeutic potential of gene therapy in SPG4 mouse models.
Note: Study plan and capsid selection may be updated depending on PHP.eB compatibility and rat model outcomes.
Status: On hold pending strategic review
Purpose: Evaluate gene therapy effects in mouse models with gain-of-function SPAST mutations.
Note: Further testing to be reevaluated following results of Aim 2.
Status: On hold pending rat model outcomes and capsid compatibility.
Purpose: Previously proposed to assess gene therapy effects in a large animal model.
Note: Due to the switch to PHP.eB (which is not compatible with large animals), this aim is no longer prioritized and may be removed depending on regulatory feedback.