Project AAV9 Gene Therapy
What is Gene Therapy?
DNA (Deoxyribonucleic acid) is a molecule that stores genetic information. Genes are the pieces of genetic information that the cells use to make protein. Gene Therapy is the process of fixing the dysfunctional gene or in other words the faulty code in DNA is fixed. The dysfunctional gene or flawed mutation is removed, and a new healthy gene replaces the faulty one.
AAV9 is particularly effective as it can penetrate the blood-brain barrier and infect various cell types, including neurons, without triggering significant immune responses or harmful effects. This makes AAV9 a promising method for delivering normal copies of the SPAST gene to cells impacted by SPG4.
Project Overview:
This multi-phase research project, involving four institutions, is focused on developing a gene therapy for SPG4 by utilizing AAV9 vectors to deliver normal SPAST genes. The outlined aims detail the essential studies needed to support a Pre-Investigational New Drug Application (Pre-IND) meeting with the FDA, the way for a phase I/II clinical trial.
The four institutions—Boston Children's Hospital, Drexel University College of Medicine, UMass Chan Medical School, and the University of Wisconsin—collaborated to advance the AAV9 Gene Therapy Project for SPG4. The Lilly and Blair Foundation is proud to support this important initiative in partnership with the CureSPG4 Foundation and the Laidlaw Family, starting in July 2024.
The Lilly and Blair Foundation is backing this significant initiative in collaboration with the CureSPG4 Foundation and the Laidlaw Family, that began in July 2024. It’s estimated that in total, this project will cost $3M. Maurya Koduri Foundation is dedicated to supporting the next phases of the Gene Therapy Project, starting with Aim 4, while awaiting the results from Aims 1 through 3 and the next round of funding to proceed.
Aim 1: Testing AAV9-SPAST Vectors in Patient Cells ($43,600)
Aim 2: Therapeutic Effect in a Rat Model of SPG4 ($142,875)
Aim 3: Prepare for Clinical Trials ($82,992)
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 spastic function.
Timeline: Approximately 6 months
Outcome: Determine feasibility of AAV9 vectors for potential therapeutic use based on cellular responses.
Aim 4: Assess AAV9 SPAST Vectors in patient-derived neurons ($162,500)
Purpose: Evaluate the efficacy of AAV9-SPAST vectors in correcting spastic deficiency in neurons derived from SPG4 patients.
Experimental Design: Patient-derived neurons will be exposed to AAV9 vectors to assess gene delivery efficiency, spastic expression levels, and functional restoration.
Timeline: Dependent on completion of related experiments
Outcome: Determine suitability of AAV9 vectors for treating neuronal cells effected by SPG4
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.
Aim 5: Preclinical studies in SPG4 mouse model ($166,000)
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: Collect essential preclinical data and establish protocol for future clinical trials of AAV9 SPAST gene therapy.
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.
Aim 6: Study AAV-SPAST Vectors in Gain-of-Function Mouse Model ($144,406)
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.
Aim 7: Therapeutic Experiments in SPG4 Cattle Model ($193,500)
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.
Meet the Gene therapy project team
Darius Ebrahimi- Fakhari, MD, PhD
Liang Oscar Qiang, MD, PhD
