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Intrathecal Gene Therapy for Giant Axonal Neuropathy.
Bharucha-Goebel, Diana X; Todd, Joshua J; Saade, Dimah; Norato, Gina; Jain, Minal; Lehky, Tanya; Bailey, Rachel M; Chichester, Jessica A; Calcedo, Roberto; Armao, Diane; Foley, A Reghan; Mohassel, Payam; Tesfaye, Eshetu; Carlin, Bradley P; Seremula, Beth; Waite, Melissa; Zein, Wadih M; Huryn, Laryssa A; Crawford, Thomas O; Sumner, Charlotte J; Hoke, Ahmet; Heiss, John D; Charnas, Lawrence; Hooper, Jody E; Bouldin, Thomas W; Kang, Elizabeth M; Rybin, Denis; Gray, Steven J; Bönnemann, Carsten G.
Affiliation
  • Bharucha-Goebel DX; 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
  • Todd JJ; 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
  • Saade D; 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
  • Norato G; 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
  • Jain M; 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
  • Lehky T; 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
  • Bailey RM; 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
  • Chichester JA; 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
  • Calcedo R; 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
  • Armao D; 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
  • Foley AR; 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
  • Mohassel P; 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
  • Tesfaye E; 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
  • Carlin BP; 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
  • Seremula B; 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
  • Waite M; 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
  • Zein WM; 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
  • Huryn LA; 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
  • Crawford TO; 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
  • Sumner CJ; 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
  • Hoke A; 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
  • Heiss JD; 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
  • Charnas L; 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
  • Hooper JE; 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
  • Bouldin TW; 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
  • Kang EM; 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
  • Rybin D; 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
  • Gray SJ; 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
  • Bönnemann CG; 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
N Engl J Med ; 390(12): 1092-1104, 2024 03 21.
Article de En | MEDLINE | ID: mdl-38507752
ABSTRACT

BACKGROUND:

Giant axonal neuropathy is a rare, autosomal recessive, pediatric, polysymptomatic, neurodegenerative disorder caused by biallelic loss-of-function variants in GAN, the gene encoding gigaxonin.

METHODS:

We 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.

RESULTS:

One 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.

CONCLUSIONS:

Intrathecal 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.).
Sujet(s)

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Thérapie génétique / Techniques de transfert de gènes / Neuropathie à axones géants Limites: Child / Humans Langue: En Journal: N Engl J Med Année: 2024 Type de document: Article

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Thérapie génétique / Techniques de transfert de gènes / Neuropathie à axones géants Limites: Child / Humans Langue: En Journal: N Engl J Med Année: 2024 Type de document: Article