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Intrathecal Gene Therapy for Giant Axonal Neuropathy
Diana X Bharucha-Goebel1, Joshua J Todd1, Dimah Saade1
1From the Neuromuscular and Neurogenetic Disorders of Childhood Section (D.X.B.-G., J.J.T., D.S., A.R.F., P.M., C.G.B), National Institute of Neurological Disorders and Stroke (G.N., T.L., J.D.H.), the Rehabilitation Medicine Department, Clinical Center (M.J., M.W.), National Eye Institute (W.M.Z., L.A.H.), and the National Institute of Allergy and Infectious Diseases, Division of Intramural Research (E.M.K.), National Institutes of Health, Bethesda, and the Departments of Neurology (C.J.S., A.H., T.O.C.), Neuroscience (C.J.S., A.H.), and Pediatrics (T.O.C.), Johns Hopkins University School of Medicine, Baltimore - all in Maryland; Children's National Hospital, Washington, DC (D.X.B.-G.); the University of Iowa, Iowa City (D.S.); the Department of Pediatrics and Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center (R.M.B, S.J.G.), and Taysha Gene Therapies (E.T.) - both in Dallas; the Gene Therapy Program, University of Pennsylvania Perelman School of Medicine, Philadelphia (J.A.C.), Cencora PharmaLex, Conshohocken (B.P.C.), and Atorus Research, Newtown Square (B.S.) - all in Pennsylvania; Affinia Therapeutics, Waltham (R.C.), and the Rare Disease Research Unit, Pfizer, Cambridge (L.C., D.R.) - both in Massachusetts; the Departments of Pathology and Laboratory Medicine (D.A., T.W.B.) and Radiology (D.A.), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill; and the Department of Pathology, Stanford University School of Medicine, Stanford, CA (J.E.H.).
This study explored gene therapy for giant axonal neuropathy, finding that intrathecal scAAV9/JeT-GAN showed potential motor function benefits at certain doses. Further research is needed to confirm safety and efficacy in treating this rare neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Pediatrics
Background:
- Giant axonal neuropathy (GAN) is a rare, inherited neurodegenerative disorder affecting children.
- It is caused by mutations in the GAN gene, leading to gigaxonin deficiency.
- The condition presents with multiple symptoms impacting the nervous system.
Purpose of the Study:
- To evaluate the safety and efficacy of intrathecal gene therapy using scAAV9/JeT-GAN in children with GAN.
- To determine the optimal dose for slowing disease progression based on motor function measures.
Main Methods:
- A dose-escalation study involving 14 pediatric participants with GAN.
- Administration of four different intrathecal doses of scAAV9/JeT-GAN.
- Primary endpoint: safety; Secondary endpoint: slowing of motor function decline over 1 year using the Motor Function Measure (MFM).
Main Results:
- The highest dose (1.8×10^14 vg) achieved a 99% probability of slowing MFM score decline, exceeding the efficacy threshold.
- Some participants showed improved or stabilized sensory-nerve action potential amplitudes.
- Adverse events were observed, with one serious event possibly related to treatment.
Conclusions:
- Intrathecal scAAV9/JeT-GAN gene therapy demonstrated potential benefits in motor function and nerve conduction in children with GAN.
- While generally well-tolerated, adverse events warrant careful monitoring.
- Further investigation is necessary to establish the long-term safety and efficacy of this gene therapy approach for GAN.
