AAV9 Gene Therapy Project for SPG4

The Lilly and Blair Foundation is proud to co-fund the AAV9 Gene Therapy Project for SPG4 – an unprecedented, multi-institutional effort to develop a cure for SPG4 and advance it to clinical trials within the next two 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 an AAV9-based gene therapy for SPG4 that could be ready for a first-in-human clinical trial in approximately two years. The total project budget is 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.

About SPG4
SPG4 is caused by mutations in the SPAST gene, which encodes the protein spastin. Spastin is essential for the maintenance of nerve cells (neurons), especially the long neurons that run from the brain down the spinal cord to the legs. When SPAST is mutated, the resulting spastin protein is dysfunctional or absent, leading to impaired microtubule dynamics in neurons. Over time, this causes degeneration of those long nerve fibers that control muscle movement. Patients with SPG4 experience worsening muscle stiffness (spasticity) and weakness in their legs, leading to difficulty walking. In childhood-onset de novo cases, the symptoms are often far more severe than adult-onset cases – the disease can progress upward to affect the torso, arms, speech, and even cognition in some children. Currently, there is no therapy that alters this disease course.

About the AAV9 Vector Approach

AAV9 stands for adeno-associated virus serotype 9. AAV is a small virus that has been engineered by scientists as a safe gene delivery tool. AAV9 is particularly useful for neurological diseases because it can cross the blood-brain barrier and deliver genes to many types of cells, including motor neurons, with minimal immune reaction. In this project, AAV9 vectors are being used to carry normal SPAST genes into the cells of an SPG4 patient. By introducing healthy copies of the gene, the therapy aims to enable the patient’s cells to produce functional spastin protein again. This approach could compensate for the mutated gene’s effects – essentially replacing or bypassing the disease-causing gene. Notably, because it supplies a working SPAST gene, it doesn’t matter which mutation a patient has; this therapy could help anyone with SPG4.

Project Status

As a result of the Second Scientific Symposium on De Novo SPG4 hosted by The Lilly and Blair Foundation and the National Institutes of Health (NIH), the four institutions below were able to connect and forge a path forward to establish the AAV9 Gene Therapy Project for SPG4. In July 2024, The Lilly and Blair Foundation – in partnership with the Cure SPG4 Foundation and the Laidlaw family – fully funded the first three aims of the project. Work on these aims is now underway. We will continue to fundraise for the subsequent aims (4 through 7) to ensure the project’s completion. We are committed to providing updates on research progress as milestones are achieved..

Essential Study Aims

In July 2024, The Lilly and Blair Foundation provided funding for the first three aims of the AAV9 Gene Therapy Project for SPG4. These aims - to be completed by July 2025 - will generate the minimal data necessary to support a Pre-IND meeting for a Phase I/II clinical trial.
View the details of the first three project aims below, as well as information on the remaining project aims (four through seven) that provide important aspects of therapeutic efficacy for evaluation prior to a clinical trial.

Aim 1: Testing AAC9-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

Purpose: Evaluate the ability of AAV9 vectors to deliver and express normal SPAST genes in cells derived from SPG4 patients.
Experimental Design: Patient-derived cells will be exposed to AAV9 vectors carrying functional SPAST genes to assess gene delivery efficiency and restoration of spastin function.

Timeline: Approximately 6 months
Outcome: Determine feasibility of AAV9 vectors for potential therapeutic use based on cellular responses.
Purpose: Assess the therapeutic potential of AAV9-SPAST vectors in improving motor function and neurological symptoms in an animal model of SPG4.
Experimental Design: SPG4 rat models deficient in spastin will receive AAV9 vectors to deliver normal SPAST genes. Motor function and disease progression will be monitored to evaluate therapeutic efficacy.

Timeline: Initial assessment at 6 weeks of age; further assessment at 8 months or humane endpoint
Outcome: Provide preclinical evidence supporting advancement to further animal studies or clinical trials.
Purpose: Collect essential preclinical data and establish protocols necessary for future clinical trials of AAV9-SPAST gene therapy in SPG4 patients.
Study Design: Document disease progression in SPG4 patients, establish a biobank for research samples, and develop a comprehensive clinical trial protocol.

Timeline: Ongoing with specific milestones, including longitudinal data collection over 12 months
Objective: Lay groundwork for transitioning AAV9-SPAST gene therapy from preclinical research to clinical application.
Purpose: Evaluate the efficacy of AAV9-SPAST vectors in correcting spastin deficiency in neurons derived from SPG4 patients.
Experimental Design: Patient-derived neurons will be exposed to AAV9 vectors to assess gene delivery efficiency, spastin expression levels, and functional restoration.

Timeline: Dependent on completion of related experiments
Outcome: Determine suitability of AAV9 vectors for treating neuronal cells affected by SPG4.
Purpose: Investigate the therapeutic potential of AAV9-SPAST vectors in a mouse model of SPG4.
Experimental Design: SPG4 mice lacking functional spastin will receive AAV9 vectors to evaluate effects on disease progression, motor function, and neurological symptoms.

Timeline: Work ongoing with specific tasks, such as behavioral and histological analyses
Outcome: Assess feasibility of AAV9 gene therapy in a mouse model as a precursor to human trials.
Purpose: Evaluate effectiveness of AAV9-SPAST vectors in correcting disease symptoms in a specific SPG4 mouse model with gain-of-function mutations.
Experimental Design: Mice expressing mutant spastin genes will be treated with AAV9 vectors to study gene knockdown and replacement effects on disease phenotype.

Timeline: Assessments at 3 months and 9 months or humane endpoint
Outcome: Assess therapeutic potential and optimize dosing strategies for AAV9-SPAST gene therapy.
Purpose: Test the efficacy of AAV9-SPAST gene therapy in a large animal model of SPG4 to assess potential treatments for human application.
Experimental Design: Calves with SPG4 mutations will receive AAV9 vectors to evaluate effects on disease symptoms and survival.

Timeline: Expected generation of affected homozygous animals in Spring 2025 for testing
Outcome: Determine translational potential of AAV9-SPAST gene therapy in larger animals before human clinical trials.