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<p>The dual rAAVrh8-<i>HEXA</i> and rAAVrh8-<i>HEXB</i> vector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay–Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on an <i>n</i> = 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay–Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h<sup>−1</sup> ml<sup>−1</sup>, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3–3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration: <a href="https://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT04669535">NCT04669535</a> and <a href="https://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT06614569">NCT06614569</a>.</p>

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Dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis: a phase 1/2 trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月15日

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  • Florian Eichler,
  • Oguz I. Cataltepe,
  • Rrita Daci,
  • Ajit S. Puri,
  • Toloo Taghian,
  • Xuntian Jiang,
  • Mohammed Salman Shazeeb,
  • Anna Kuhn,
  • Asma Hader,
  • Hakki Celik,
  • Zeynep Vardar,
  • Connor J. Lewis,
  • Rebecca Artinian,
  • Amanda Nagy,
  • Behroze Vachha,
  • Robert Thompson,
  • Thomas Gallagher,
  • Scot Bateman,
  • Julia Parzych,
  • Spiro G. Spanakis,
  • Toby A. Vaughn,
  • Kirsten Pier,
  • Erika De Boever,
  • Mary-Alice Abbott,
  • Eleonora D′Ambrosio,
  • Danielle Kokoski,
  • Meghan Blackwood,
  • Elise Drummond,
  • Eva-Maria Ratai,
  • Elise L. Townsend,
  • Haley McLaughlin,
  • Cynthia J. Tifft,
  • Allison M. Keeler,
  • Miguel Sena-Esteves,
  • Heather L. Gray-Edwards,
  • Terence R. Flotte

摘要

The dual rAAVrh8-HEXA and rAAVrh8-HEXB vector can restore central nervous system hexosaminidase (Hex) enzyme activity, decrease GM2 levels in cerebrospinal fluid and rescue phenotypic consequences of GM2 gangliosidosis, Tay–Sachs and Sandhoff diseases in animal models following simultaneous bi-thalamic (BiT) injections. Following up on an n = 2 expanded access trial, we initiated a phase 1/2, single-dose, dose-escalation of combined BiT, intra-cisterna magna and intrathecal infusion in children with Tay–Sachs and Sandhoff diseases (six infantile, three juvenile). The BiT injection volume and vector dose were doubled between four cohorts, with the lowest dose matching the earlier expanded access trial. Cerebrospinal fluid HexA enzyme activity, serum total Hex activity and GM2 levels showed a dose-dependent biochemical correction of the disease. Serum Hex activity surpassed 40 nmol h−1 ml−1, two times the lower limit of normal, and neuroimaging demonstrated increased fiber tracts. Correction was greatest at 12 weeks, but in decline by 24 weeks postdosing. Infantile patients experienced global clinical stabilization and prolonged oral feeding without aspiration until 3–3.5 years. Seizures had a later onset, were less frequent, less severe and more responsive to anti-convulsant medication. Adverse events were rare in infantile patients, but worsening dystonia was observed in juvenile patients, who were excluded from ongoing enrollment. ClinicalTrials.gov registration: NCT04669535 and NCT06614569.