First-in-human nuclease-free homologous recombination-dependent gene editing in pediatric patients with methylmalonic acidemia: results of a phase 1/2 study.
The SUNRISE study showed that while gene editing can increase MMUT expression, it did not effectively normalize serum methylmalonic acid levels, and safety concerns were raised due to treatment-emergent adverse events.
Where it sits
this study against the rest of the l-carnitine (levocarnitine) corpusSummary and findings
This study evaluated the safety and tolerability of liver-targeted hLB-001 in four pediatric participants with methylmalonic acidemia (MMA). All participants experienced at least one treatment-emergent adverse event, and the study was terminated due to lack of efficacy. MMUT expression increased in two participants over two years, but serum methylmalonic acid levels remained abnormal in all participants.
Abstract
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: NCT04581785Target journal: Gene Therapy (Springer Nature).
Background
This paper addresses the clinical question of gene editing for treating methylmalonic acidemia, a metabolic disorder. Previous studies have explored various gene therapy approaches, but this study is significant as it presents a first-in-human trial using a nuclease-free method. Understanding the safety and feasibility of such interventions is crucial for advancing treatment options in pediatric populations.
Methods
The study design is a phase 1/2 trial involving pediatric patients diagnosed with methylmalonic acidemia. Specific details regarding the population size (n), dosing regimen, duration of treatment, and primary versus secondary outcome measures were not reported in the abstract.
Results
Not reported in abstract.
Interpretation
Due to the lack of reported results, it is challenging to compare this study's findings with prior literature or to assess the clinical significance of the intervention. Without specific data, the implications for practice remain unclear, and potential confounding factors cannot be evaluated.
Key findings
- Not reported in abstract.
Limitations
- Not reported in abstract.