AAV9 Gene Therapy Project for SPG4

The Lilly and Blair Foundation is proud to fund the AAV9 Gene Therapy Project for SPG4. Read more about the research project below and donate now to support this critical work on the path to a clinical trial. 100 percent of donations go directly towards research projects and programs dedicated to finding a treatment or cure for childhood-onset, de novo spastic paraplegia.

Donate Now

Project Overview

Introduction

The AAV9 Gene Therapy Project for SPG4 is a collaborative initiative between Boston Children’s Hospital, Drexel University College of Medicine, UMass Chan Medical Center and The University of Wisconsin-Madison. focused on advancing a treatment or cure for SPG4 to clinical trials within two years. The estimated cost of this project is substantial - nearly $3M, but the potential impact is extraordinary. The anticipated outcomes of this project are agnostic to the variant or mutation. Should a treatment or cure come from this research, it would be applicable for all persons impacted by SPG4, transforming the lives of thousands both now and in the future.

About SPG4

SPG4 is caused by mutations in the SPAST gene, which encodes the spastin protein. Spastin is crucial for maintaining nerve cell function, particularly in the long nerve fibers that connect the brain and spinal cord to muscles in the legs.

Mutations in the SPAST gene lead to dysfunctional spastin protein. This results in impaired microtubule dynamics and axonal transport, ultimately causing degeneration of the nerve fibers that control muscle movement. SPG4 patients experience spasticity and difficulty walking that progressively gets worse as the nerve fibers degenerate. Childhood-onset, de novo patients experience symptoms that tend to be much more severe and can ascend to the core, arms, speech and cognition.

About the AAV9 Vector Gene Therapy Project for SPG4

AAV9 (Adeno-Associated Virus serotype 9) vectors are vehicles used in gene therapy to deliver therapeutic genes into target cells. AAV9 is particularly effective because it can cross the blood-brain barrier and infect a wide range of cell types, including neurons, without causing significant immune responses or pathogenic effects. This makes AAV9 a promising tool for delivering normal copies of the SPAST gene into cells affected by SPG4.

This phased, multi-institutional research project aims to develop a gene therapy treatment for SPG4 using AAV9 vectors to deliver normal SPAST genes. Each aim below outlines the minimum studies necessary to support a Pre-Investigational New Drug Application (Pre-IND) meeting with the FDA in preparation for a phase I/II clinical trial.

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. The Lilly and Blair Foundation is proud to fund this incredible work in collaboration with the CureSPG4 Foundation and the Laidlaw Family. In July of 2024, we fully funded the first three project aims and we look forward to posting research updates here as they become available.

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.