Correction Of Biochemical Abnormalities Research Articles

Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice

Maple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. Treatment for MSUD represents an unmet need because the current treatment with life-long low-protein diet is challenging to maintain, and despite treatment the risk of acute decompensations and neuropsychiatric symptoms remains. Here, based on significant liver contribution to the catabolism of the branched chain amino acid leucine, we develop a liver-directed adeno-associated virus (AAV8) gene therapy for MSUD. We establish and characterize the Bckdha (branched chain keto acid dehydrogenase a)−/− mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. Animals were treated at P0 with intravenous human BCKDHA AAV8 vectors under the control of either a ubiquitous or a liver-specific promoter. BCKDHA gene transfer rescued the lethal phenotype. While the use of a ubiquitous promoter fully and sustainably rescued the disease (long-term survival, normal phenotype and correction of biochemical abnormalities), liver-specific expression of BCKDHA led to partial, though sustained rescue. Here we show efficacy of gene therapy for MSUD demonstrating its potential for clinical translation.

Associations between circulating bone-derived hormones osteocalcin, lipocalin 2, and glucose metabolism in patients with acromegaly

Objective The aim of this study was to examine the change of serum bone-derived hormones osteocalcin and lipocalin 2 (LCN2) level in patients with active acromegaly, and to further investigate the potential role of osteocalcin and LCN2 in glucose metabolism. Methods Fifty consecutive patients diagnosed as acromegaly in Nanjing Drum Tower Hospital from December 2016 to August 2018 were recruited. Of those, 41 patients after operations with complete follow-up data were also included. 30 sex, age, and body mass index matched healthy persons as normal controls. Serum osteocalcin and LCN2 levels were compared between controls and patients with acromegaly, as well as at pre- and post- operation periods. Univariate and multivariate linear regression analyses were used to investigate the correlation between bone-derived hormones and glucose metabolism indexes and to determine the independent associations between variables. Results Compared with normal controls, serum osteocalcin increased [(55.45±34.02 vs 19.46±6.69)ng/ml, P 0.05). After operation, with the decrease of serum growth hormone (GH) and insulin-like growth factor 1 (IGF-1), serum osteocalcin level decreased [24.79(18.39, 32.59) vs 43.51(26.73, 65.66)ng/ml, P<0.01] and LCN2 level increased [(45.15±15.33 vs 37.03±9.73)ng/ml, P<0.05] significantly compare to pre-operation levels. In a multivariate linear stepwise regression analysis, lean mass was shown to be the only positive predictor for LCN2 (β=0.44, P=0.015) and elevated serum IGF-1 was a positive predictor for osteocalcin (β=0.512, P<0.01). In the multivariate models, low LCN2 (β=-0.398, P=0.017) and elevated serum osteocalcin (β=0.553, P=0.001) were predictors for AUCINS, osteocalcin was a positive predictor of HOMA- β (β=0.519, P=0.004). GH (β=0.294, P=0.029) and IGF-1(β = 0.428, P=0.002) were all identified as positive predictors of HOMA-IR during multivariate testing in acromegaly patients. Conclusions Acromegaly patients had increased osteocalcin and decreased LCN2 serum levels, and corresponding alteration was detected with the correction of biochemical abnormalities. Serum osteocalcin and LCN2 were predictors of β-cell function in acromegaly patients. This study adds new evidence for the role of bone in regulating glucose metabolism in acromegaly. Key words: Acromegaly; Osteocalcin; Lipocalin 2; Glucose metabolism

Correction of biochemical abnormalities and gene expression associated with improved muscle function in a phase I/II clinical trial of clenbuterol in Pompe disease patients stably treated with ERT

Correction of biochemical abnormalities and gene expression associated with improved muscle function in a phase I/II clinical trial of clenbuterol in Pompe disease patients stably treated with ERT

Metabolic encephalopathies in foals – pay attention to the serum biochemistry panel!

SummaryCareful assessment of the biochemistry panel and familiarity with normal biochemistry values for neonatal foals is imperative in the workup of any critically ill neonate, particularly those with neurological signs. The importance of rapidity of change compared to the absolute value of the biochemical abnormality must be emphasised. Serial biochemical panels ideally assist in assessing rapidity of change. Many foals can have severe biochemical derangements in the absence of seizures. Identifying values that are significantly out of range should spur immediate therapy to correct them and potentially additional diagnostic testing to determine the cause of the abnormalities. A temporal relationship between correction of biochemical abnormalities and resolution of seizures and encephalopathic signs supports causation.

Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of the acid hydrolase beta-glucuronidase. MPS VII mice develop progressive lysosomal accumulation of glycosaminoglycans (GAGs) within multiple organs, including the brain. Using this animal model, we compared two plasmid gene administration techniques: muscle electrotransfer and liver-directed transfer using hydrodynamic injection. We have evaluated both the expression kinetics and the biodistribution of beta-glucuronidase activity after gene transfer, as well as the correction of biochemical abnormalities in various organs. This study shows that MPS VII mice treated with a plasmid-bearing mouse beta-glucuronidase cDNA, acquire the ability to produce the beta-glucuronidase enzyme for an extended period of time. The liver seemed to be more appropriate than the muscle as a target organ to enable enzyme secretion into the systemic circulation. A beneficial effect on the MPS VII pathology was also observed, as liver-directed gene transfer led to the correction of secondary enzymatic elevations and to the reduction of GAGs storage in peripheral tissues and brain, as well as to histological correction in many tissues. This work is one of the first examples showing that non-viral plasmid DNA delivery can lead to improvements in both peripheral and brain manifestations of MPS VII disease. It confirms the potential of non-viral systemic gene transfer strategy in neurological lysosomal disorders.

AAV Vector-mediated Reversal of Hypoglycemia in Canine and Murine Glycogen Storage Disease Type Ia

Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to optimize liver tropism. Survival was prolonged in 2-week-old G6Pase (-/-) mice by 600-fold fewer AAV2/8 vector particles (vp), in comparison to previous experiments involving this model (2 x 10(9) vp; 3 x 10(11) vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 x 10(13) vp/kg). The AAV2/8 vector uniquely prevented hypoglycemia during fasting and fully corrected liver G6Pase deficiency in GSD-Ia mice and dogs. The AAV2/8 vector has prolonged survival in three GSD-Ia dogs to >11 months, which validated this strategy in the large animal model for GSD-Ia. Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver. Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor (HGF) in GSD-Ia mice. These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector-mediated gene therapy for GSD-Ia.

Bartter syndrome in a neonate: early treatment with indomethacin

The neonatal form of Bartter syndrome is characterized by intrauterine onset of polyuria leading to severe polyhydramnios. We report a patient with the early onset of the syndrome and a similar history in a previous sibling who died in early neonatal life. The patient is a female product of 33 weeks of gestation complicated by severe polyhydramnios. Her birth weight was 2,100 g. Polyuria led to severe dehydration on the 3rd day of life. Laboratory studies showed hypokalemia, hyponatremia, and elevated plasma levels of renin and aldosterone. Hypercalciuria was associated with echographic evidence of nephrocalcinosis. Indomethacin therapy resulted in a significant reduction in urine volume and correction of biochemical abnormalities. Growth and development are satisfactory after 4 years of indomethacin therapy, but nephrocalcinosis remains unchanged.

A far advanced case of gyrate atrophy in a 12‐year‐old girl

Gyrate atrophy (GA; McKusick 25887) is a progressive chorioretinal dystrophy with an autosomal recessive mode of inheritance. In this disorder there is a deficiency of the mitochondrial matrix enzyme ornithine-f-aminotransferase (OAT). Ocular symptoms usually present late in the first decade of life. Ophthalmological findings include myopia, constricted visual fields, elevated dark adaptation thresholds (night blindness), very small or absent electroretinographic responses, and characteristic patchy chorioretinal atrophy distributed circumferentially around the peripheral fundus. Gradually the round patches of atrophy coalesce to form widespread chorioretinal atrophy extending to the posterior pole. Cataracts develop requiring surgical intervention, and eventually blindness occurs due to progressive loss of functional retina at the age of 40 to 50 (Valle and Simell, 1989). Plasma ornithine levels range from 400 to 1400/~mol/L, and 0.5 to 10mmol of ornithine is excreted daily. Glutamate, glutamine, lysine, creatine and creatinine concentrations in plasma are modestly reduced. The pathophysiological mechanism responsible for the chorioretinal dystrophy in GA is not known. Hyperornithinaemia or associated secondary metabolic abnormalities may play an important role, but until the pathophysiology is understood, there is no assurance that correction of biochemical abnormalities in plasma will actually be beneficial (Berson et al., 1981). Four general therapeutic approaches have been used: pharmacological doses of pyridoxine, reducing the intake of arginine and administration of creatine or proline. In this paper we described a 12-year-old patient with night blindness and myopia as the first symptoms of gyrate atrophy with ornithinaemia.

Evaluation of three oral rehydration solutions designed for use in developed communities

One hundred and sixteen children (less than 2 years old) admitted to a London hospital with acute gastroenteritis were randomized to receive either an oral rehydration solution (ORS) with low sodium and high glucose concentration (Na+ 35, glucose 200 mmol/L), an ORS with a high sodium but low glucose concentration (Na+ 60, glucose 111 mmol/L), or an ORS containing glycine and a glucose polymer (Na+ 50, glucose 50, glycine 50 mmol/L). Clinical, biochemical and haematological features of the three groups were similar on admission. Rotavirus was common (31%); the majority of children had minimal dehydration or acid-base disturbance. The clinical outcome, including ORS intake, prevention of dehydration, rehydration, and duration of hospital stay was similar in the three treatment groups. All initial electrolyte abnormalities were corrected; no child developed hypernatraemia or hyponatraemia. At 24 h, the mean serum urea was higher in those who received the ORS containing glycine than in other groups, and it had not fallen significantly since admission. Eighteen per cent of children had carbohydrate intolerance: four children with greater than or equal to 2% reducing substances in their stool had all received ORS with a high glucose content and had numerous watery green stools containing rotavirus. All ORS solutions were safe and effective for rehydration and correction of biochemical abnormalities, however carbohydrate intolerance was more prevalent in children who received the ORS with a high glucose content.