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Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively. mRNA therapeutics delivered via lipid nanoparticles are being developed for the treatment of metabolic diseases caused by protein deficiency. Here, the authors use preclinical data to develop translational PK/PD models, which scaled allometrically to humans to predict starting doses for first-in-human clinical studies for in propionic acidemia, methylmalonic acidemia, and phenylketonuria.

Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of ~ 1: 50,000 and PA of ~ 1:100-000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B 12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.

Background Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016. Results During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 ( n  = 26), 1 cobalamin B was detected and that for PA cases ( n  = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH 3 values as well as a lower pH value ( p  < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6–6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) ( p  < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% ( p  < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT ( p  = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 ( p  = 0.07). Conclusion MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious.

Propionic acidemia is an inborn error of metabolism caused by mutations in either the PCCA or PCCB genes. Patients with propionic acidemia experience a range of complications, including life-threatening cardiac dysfunctions. However, the pathological mechanisms underlying propionic acidemia-associated cardiac diseases remain largely unknown. To gain insights into the metabolic alterations in propionic acidemia, we studied human induced pluripotent stem cell-derived cardiomyocytes generated from a patient with propionic acidemia with two pathogenic PCCA mutations ( p.Cys616_Val633del and p.Gly477Glufs9* ) and from a healthy individual. Using stable isotope-based metabolic flux analysis, we confirmed that the PCCA mutations lead to impaired propionyl-CoA carboxylase activity in human induced pluripotent stem cell-derived cardiomyocytes. In addition to being converted to propionylcarnitine, the accumulated propionyl-CoA can also be hydrolyzed to propionate and exported out of the cell, serving as a secondary “pressure valve” to regulate cellular propionyl-CoA levels. Interestingly, the deficiency of propionyl-CoA carboxylase was found to shift fuel metabolism from fatty acid oxidation to increased glucose metabolism human in induced pluripotent stem cell-derived cardiomyocytes from patients with propionic acidemia. This metabolic switch is less energy-efficient and may contribute to the development of chronic cardiac dysfunction in patients with propionic acidemia.

Propionic acidaemia is a rare disorder caused by defects in the propionyl-coenzyme A carboxylase α or β (PCCA or PCCB) subunits that leads to an accumulation of toxic metabolites and to recurrent, life-threatening metabolic decompensation events. Here we report interim analyses of a first-in-human, phase 1/2, open-label, dose-optimization study and an extension study evaluating the safety and efficacy of mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. As of 31 May 2023, 16 participants were enrolled across 5 dose cohorts. Twelve of the 16 participants completed the dose-optimization study and enrolled in the extension study. A total of 346 intravenous doses of mRNA-3927 were administered over a total of 15.69 person-years of treatment. No dose-limiting toxicities occurred. Treatment-emergent adverse events were reported in 15 out of the 16 (93.8%) participants. Preliminary analysis suggests an increase in the exposure to mRNA-3927 with dose escalation, and a 70% reduction in the risk of metabolic decompensation events among 8 participants who reported them in the 12-month pretreatment period. Interim data from a clinical trial of mRNA-3927—an mRNA therapeutic for propionic acidaemia—provide early indications of the safety and efficacy of the treatment, and suggest that this approach might be applicable to other rare diseases.

Background Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited. Study design/methods Clinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients’ and their families’ quality of life was assessed. Results The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents’ point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls. Conclusion Our data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.

Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases. Hyperammonemia occurs in liver diseases affecting ureagenesis, and is life-threatening. Here, the authors show that liver UDP-GlcNAc is increased during hyperammonemia, leading to O-GlcNAcylation of the rate-limiting ureagenesis enzyme CPS1, that enhanced ureagenesis and ammonia detoxification. They also showed that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease.

Mutations in the mitochondrial enzyme propionyl-CoA carboxylase (PCC) cause propionic aciduria (PA). Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD. The pathophysiological mechanisms of CKD are unclear. We investigated the renal phenotype of a hypomorphic murine PA model ( Pcca -/- (A138T) ) to identify CKD-driving mechanisms. Pcca -/- (A138T) mice show elevated retention parameters and express markers of kidney damage progressing with time. Morphological assessment of the Pcca -/- (A138T) mouse kidneys indicated partial flattening of tubular epithelial cells and focal tubular-cystic dilation. We observed altered renal mitochondrial ultrastructure and mechanisms acting against oxidative stress were active. LC–MS/MS analysis confirmed disease-specific metabolic signatures and revealed disturbances in mitochondrial energy generation via the TCA cycle. Our investigations revealed altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy. We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission. Our results suggest that impairment of mitochondrial homeostasis and quality control are involved in CKD development in PA. Therapeutic targeting of the identified pathways might help to ameliorate CKD in addition to the current treatment strategies.

Background Propionic acidemia (PA) is a rare autosomal recessive disorder of metabolism caused by mutations in the PCCA or PCCB gene, leading to propionyl CoA carboxylase (PCC) enzyme deficiencies. Most PA patients present variable clinical phenotypes and severity in the neonatal or infant period, with only a few developing symptoms after infancy. This report describes a PA patient with an adult-onset phenotype and a novel compound heterozygous mutation in the PCCB gene. To further explore the genotype–phenotype correlations in late-onset PA, we performed a literature review focusing on and summarizing 11 patients with PCC gene mutations who had the first onset and/or the definite diagnosis after infancy. Case presentation A 21-year-old PA patient presented with weakness of four limbs, gait abnormalities, two episodes of seizures, mental and behavior disorders after severe vomiting. Magnetic Resonance Imaging (MRI) demonstrated sustained bilateral caudate head and putamen symmetrical hyperintensity. Biochemical investigations revealed plasma amino and urine values correlating with a PA profile. Genetic analysis confirmed novel compound heterozygous variants in PCCB , with a newly-found pathogenic mutation (c.467T>C) and the c.1316A>G mutation associated with pathogenicity. Conclusion We identified a novel compound heterozygous mutation in the PCCB gene causing late-onset PA. Patients carrying mutations in the PCCB gene tend to develop late-onset PA and present neuropsychiatric symptoms and/or signs. Further molecular biological research is needed to explore the genotype–phenotype correlations of PA.

Background Classical organic acidurias including methylmalonic aciduria (MMA), propionic aciduria (PA) and isovaleric aciduria (IVA) are severe inborn errors of the catabolism of branched-chain amino acids and odd-numbered chain fatty acids, presenting with severe complications. Methods This study investigated the long-term outcome of 80 patients with classical organic aciduria (38 with MMA, 24 with PA and 18 with IVA) by integrating clinical, radiological, biochemical and genetic data. Results Patients were followed-up for a mean of 14 years [age 3.3-46.3 years]. PA included a greater number of patients with abnormal neurological examination (37% in PA, 24% in MMA and 0% in IVA), lower psychometric scores (abnormal evaluation at age 3 years in 61% of patients with PA versus 26% in MMA and 18% in IVA) and more frequent basal ganglia lesions (56% of patients versus 36% in MMA and 17% in IVA). All patients with IVA presented a normal neurological examination and only 1/3 presented cognitive troubles. Prognosis for MMA was intermediate. Biochemical metabolite analysis excluding acute decompensations revealed significant progressive increases of glycine, alanine and glutamine particularly in PA and possibly in MMA but no correlation with neurological outcome. A significant increase of plasma methylmalonic acid was found in MMA patients with intellectual deficiency (mean level of 199 μmol/L versus 70 μmol/L, p < 0.05), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 167 μmol/L. Urinary 3-hydroxypropionate (3-HP) levels were significantly higher in PA patients with intellectual deficiency (mean level of 68.9 μmol/mmol of creatinine versus 34.6 μmol/mmol of creatinine, p < 0.01), with an estimated significant probability of severe outcome for average levels between birth and age 6 years above 55 μmol/mmol. As for molecular analysis, prognosis of MMA patients with mutations involving the MMAA gene was better compared to patients with mutations involving the MUT gene. Conclusion Propionic aciduria had the most severe neurological prognosis. Our radiological and biochemical data are consistent with a mitochondrial toxicity mechanism. Follow-up plasma MMA and urinary 3-HP levels may have prognostic significance calling for greater efforts to optimize long-term management in these patients.