Gene therapy for organic acidemias: Lessons learned from methylmalonic and propionic acidemia

Chandler, Randy J.; Venditti, Charles P.

doi:10.1002/jimd.12665

Cited by 8 publications

(3 citation statements)

References 58 publications

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“…In some cases, despite optimized treatment, cardiac dysfunction may be progressive and require cardiac transplantation. More recently, multiple gene therapy approaches have been explored in relevant animal models [29,30]. However, experience is limited, and there is concern that the operative stress may result in a major episode of metabolic decompensation and complicate the post-operative course.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort

Passantino,

Chiellino,

Girolami

et al. 2023

Diagnostics

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Background: Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history of patients with OAs remains unresolved, specifically with regard to the impact of cardiac complications. We therefore performed a retrospective study to address this issue at our Referral Center for Pediatric Inherited Errors of Metabolism. Methods: Sixty patients with OAs (propionic (PA), methylmalonic (MMA) and isovaleric acidemias and maple syrup urine disease) diagnosed from 2000 to 2022 were systematically assessed at baseline and at follow-up. Results: Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). The presence of DCM was associated with the worst prognosis. The rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA with cardiomyopathy; 35% in MMA with cardiomyopathy; and 23% in MMA without cardiomyopathy. Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. Conclusions: Cardiac involvement was documented in about one third of children diagnosed with classical OAs, confined to PA and MMA, and was often associated with poor outcome in over 50%. Etiological diagnosis of OAs is essential in guiding management and risk stratification.

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Section: Discussionmentioning

confidence: 99%

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort

Passantino,

Chiellino,

Girolami

et al. 2023

Diagnostics

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“…Organic acidemias, especially methylmalonic (MMA) and propionic acidemias (PA), have been the targets of several preclinical gene replacement therapy studies, and they have been recently reviewed by Chandler and Venditti 56 . Whole transgene integration has been successfully performed using a promoterless AAV vector without nuclease using homologous recombination to target the albumin locus of the host genome.…”

Section: Organic Acidemiamentioning

confidence: 99%

Liver‐directed gene therapy for inherited metabolic diseases

Baruteau,

Brunetti‐Pierri,

Gissen

2024

J of Inher Metab Disea

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Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver‐directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver‐targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler–Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow‐up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver‐targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.

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“…Organic acidemias (OAs) are a group of rare autosomal recessive disorders of intermediary metabolism that result in a systemic increase in organic acids [ 1 , 2 , 3 ]. Propionate defects (PDs) are among the most common OAs and are mainly represented by methylmalonic (MMA) and propionic acidemias (PAs).…”

Section: Introductionmentioning

confidence: 99%

Hypogammaglobulinemia Class G Is Present in Compensated and Decompensated Patients with Propionate Defects, Independent of Their Nutritional Status

López-Mejía,

Vela-Amieva,

Guillén-López

et al. 2024

Nutrients

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Propionate defects (PDs) mainly include methylmalonic (MMA) and propionic acidemia (PA) defects. Lifelong PD patients progress from the compensated to the decompensated stages, the latter of which are characterized by life-threatening acidemia and hyperammonemia crises. PD patients can suffer immunocompromise, especially during the decompensation stage. There is a significant gap in the research regarding the humoral immune response in PD patients. Here, we analyzed serum immunoglobulin concentrations and hemograms across compensated and decompensated stages in PD patients. Nutritional status and crisis triggers of decompensation were also explored. Twenty patients were studied, and 25 decompensation events (DE) and 8 compensation events (CE) were recorded. Compared with those in the CE group, the IgG levels in the DE group (513.4 ± 244.5 mg/dL) were significantly lower than those in the CE group (860.8 ± 456.5 mg/dL) (p < 0.0087). The mean hemoglobin concentration was significantly lower in the DE group (11.8 g/dL) than in the CE group (13.4 g/dL) (p < 0.05). The most frequent (48%) possible decompensation trigger factor was infection. Most of the events were registered in eutrophic patients (87.9%), despite which 65.2% and 50% of patients who experienced decompensated and compensated events, respectively, presented with hypogammaglobulinemia G. These findings provide evidence of the immunodeficiency of PD patients, independent of their nutritional status. We suggest that PD patients be managed as immunocompromised independently of their nutritional status or metabolic state (compensated or decompensated).

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Gene therapy for organic acidemias: Lessons learned from methylmalonic and propionic acidemia

Cited by 8 publications

References 58 publications

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort

Liver‐directed gene therapy for inherited metabolic diseases

Hypogammaglobulinemia Class G Is Present in Compensated and Decompensated Patients with Propionate Defects, Independent of Their Nutritional Status

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