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<p>Gene-based editing can potentially correct the genetic defect in methylmalonic acidemia (MMA). SUNRISE, a first-in-human phase 1/2 open-label study, evaluated the safety/tolerability (primary endpoints) of liver-targeted hLB-001 in four pediatric participants (ages 20-114 months) with mitochondrial methylmalonyl-CoA mutase (MMUT)–deficient MMA. We designed a single-infusion adeno-associated viral capsid (hLB-001) to nondisruptively integrate functional <i>MMUT</i> at the 3′ end of the albumin (<i>ALB</i>) locus to produce both albumin and MMUT. All four participants experienced at least one treatment-emergent adverse event. Three participants had treatment-emergent serious adverse events of cytokine release syndrome (one participant) and thrombotic microangiopathy (two participants); all resolved during the trial. Biologic activity, clinical efficacy, and 1-year survival were secondary endpoints. MMUT expression (measured by 2A-tagged ALB biomarker expression) increased in two participants over two years, confirming homology-based integration and positive selection of transgenic cells. However, serum methylmalonic acid (sMMA), serum FGF21, serum methylcitric acid (sMCA), and propionate oxidation remained abnormal in all four participants. All participants were alive at 1 year and at database lock. SUNRISE was terminated due to lack of efficacy. These results provide proof-of-concept for use of liver-targeted gene editing without nucleases for MMA and other genetic metabolic disorders. ClinicalTrials.gov identifier: NCT04581785</p><p><b>Target journal</b>: <i>Gene Therapy (Springer Nature)</i></p>

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First-in-human nuclease-free homologous recombination-dependent gene editing in pediatric patients with methylmalonic acidemia: results of a phase 1/2 study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Jirair K. Bedoyan,
  • Thomas Morgan,
  • Angela Sun,
  • Hong Li,
  • Daniel Gruskin,
  • Marie Payton,
  • Frederic Chereau,
  • Eugene Scott Swenson,
  • Qun Lin,
  • Mark A. Kay,
  • Jerry Vockley

摘要

Gene-based editing can potentially correct the genetic defect in methylmalonic acidemia (MMA). SUNRISE, a first-in-human phase 1/2 open-label study, evaluated the safety/tolerability (primary endpoints) of liver-targeted hLB-001 in four pediatric participants (ages 20-114 months) with mitochondrial methylmalonyl-CoA mutase (MMUT)–deficient MMA. We designed a single-infusion adeno-associated viral capsid (hLB-001) to nondisruptively integrate functional MMUT at the 3′ end of the albumin (ALB) locus to produce both albumin and MMUT. All four participants experienced at least one treatment-emergent adverse event. Three participants had treatment-emergent serious adverse events of cytokine release syndrome (one participant) and thrombotic microangiopathy (two participants); all resolved during the trial. Biologic activity, clinical efficacy, and 1-year survival were secondary endpoints. MMUT expression (measured by 2A-tagged ALB biomarker expression) increased in two participants over two years, confirming homology-based integration and positive selection of transgenic cells. However, serum methylmalonic acid (sMMA), serum FGF21, serum methylcitric acid (sMCA), and propionate oxidation remained abnormal in all four participants. All participants were alive at 1 year and at database lock. SUNRISE was terminated due to lack of efficacy. These results provide proof-of-concept for use of liver-targeted gene editing without nucleases for MMA and other genetic metabolic disorders. ClinicalTrials.gov identifier: NCT04581785

Target journal: Gene Therapy (Springer Nature)