• Diana X Bharucha-Goebel, Joshua J Todd, Dimah Saade, Gina Norato, Minal Jain, Tanya Lehky, Rachel M Bailey, Jessica A Chichester, Roberto Calcedo, Diane Armao, A Reghan Foley, Payam Mohassel, Eshetu Tesfaye, Bradley P Carlin, Beth Seremula, Melissa Waite, Wadih M Zein, Laryssa A Huryn, Thomas O Crawford, Charlotte J Sumner, Ahmet Hoke, John D Heiss, Lawrence Charnas, Jody E Hooper, Thomas W Bouldin, Elizabeth M Kang, Denis Rybin, Steven J Gray, Carsten G Bönnemann, and GAN Trial Team.
• From 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.).
• N. Engl. J. Med. 2024 Mar 21; 390 (12): 109211041092-1104.

BackgroundGiant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin.MethodsWe conducted an intrathecal dose-escalation study of scAAV9/JeT-GAN (a self-complementary adeno-associated virus-based gene therapy containing the GAN transgene) in children with giant axonal neuropathy. Safety was the primary end point. The key secondary clinical end point was at least a 95% posterior probability of slowing the rate of change (i.e., slope) in the 32-item Motor Function Measure total percent score at 1 year after treatment, as compared with the pretreatment slope.ResultsOne of four intrathecal doses of scAAV9/JeT-GAN was administered to 14 participants - 3.5×1013 total vector genomes (vg) (in 2 participants), 1.2×1014 vg (in 4), 1.8×1014 vg (in 5), and 3.5×1014 vg (in 3). During a median observation period of 68.7 months (range, 8.6 to 90.5), of 48 serious adverse events that had occurred, 1 (fever) was possibly related to treatment; 129 of 682 adverse events were possibly related to treatment. The mean pretreatment slope in the total cohort was -7.17 percentage points per year (95% credible interval, -8.36 to -5.97). At 1 year after treatment, posterior mean changes in slope were -0.54 percentage points (95% credible interval, -7.48 to 6.28) with the 3.5×1013-vg dose, 3.23 percentage points (95% credible interval, -1.27 to 7.65) with the 1.2×1014-vg dose, 5.32 percentage points (95% credible interval, 1.07 to 9.57) with the 1.8×1014-vg dose, and 3.43 percentage points (95% credible interval, -1.89 to 8.82) with the 3.5×1014-vg dose. The corresponding posterior probabilities for slowing the slope were 44% (95% credible interval, 43 to 44); 92% (95% credible interval, 92 to 93); 99% (95% credible interval, 99 to 99), which was above the efficacy threshold; and 90% (95% credible interval, 89 to 90). Between 6 and 24 months after gene transfer, sensory-nerve action potential amplitudes increased, stopped declining, or became recordable after being absent in 6 participants but remained absent in 8.ConclusionsIntrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor function scores and other measures at some vector doses over a year. Further studies are warranted to determine the safety and efficacy of intrathecal AAV-mediated gene therapy in this disorder. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, NCT02362438.).Copyright © 2024 Massachusetts Medical Society.

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