CLINICAL PROFILE OF WILSON DISEASE IN CHILDREN IN A TERTIARY CARE CENTRE IN SOUTH INDIA

Background: Wilson disease (WD) is the most common metabolic liver disease in Indian children with late presentation mandating early identication and treatment to prevent disease related morbidity and mortality. Aim: To study the clinical prole of Wilson disease in a tertiary referral care centre for children in South India. Material & Methods: Retrospective descriptive analysis of medical records of children with Wilson disease over ve years from January 2014 to January 2018 admitted in Paediatric Gastroenterology department, Institute of child health & Hospital was done. Results: There were 75 children, 36 male 39 Female (1:1.08) with age ranging from 4 to 12 years. Clinical features include asymptomatic stage 7(9.3%). hepatic phenotype in 53 (70.6%) and neurophenotype in 15 (20%) children. Growth retardation was observed in 64 (85%), Kayser Fleischer ring in 30 (40%), Jaundice in 45 (60%), chronic liver disease in 40 (65.3%) out of which 21 (52.5%) children presented with decompensated liver disease and 14 children died during the study period with 18.7% mortality. Laboratory tests showed mean Hb 9.8 gm/dl SGOT 254 IU/L, SGPT 154 IU/L, albumin 2.2 gm/dl, low serum ceruloplasmin < 20mg/dl in 49 (65.3%), 24 hours urinary copper after D. Penicillamine challenge 680.4 µgm /day. Majority tolerated oral chelation therapy with D. Penicillamine except in 3. Conclusion:WD is the most common metabolic liver disease in children with chronic liver disease with 18.7%h mortality rate

Treatment of a metabolic liver disease by in vivo prime editing in mice

Prime editing is a highly versatile CRISPR-based genome editing technology with the potential to correct the vast majority of pathogenic mutations. However, correction of a disease phenotype in vivo in somatic tissues has not been demonstrated thus far. Here, we establish proof-of-concept for in vivo prime editing and repair the metabolic liver disease phenylketonuria (PKU) in mice. We first developed a size-reduced SpCas9 prime editor (PE) lacking the RNaseH domain of the reverse transcriptase (PE2-deltaRnH), and a linker- and NLS-optimized intein-split PE construct (PE2 p.1153) for delivery by adeno-associated virus (AAV) vectors. Systemic dual AAV-mediated delivery of this variant into the liver of neonatal mice enabled installation of a transversion mutation at the Dnmt1 locus with an average efficiency of 15%, and delivery of unsplit PE2-deltaRnH using human adenoviral vector 5 (AdV5) further increased editing rates to 58%. PE2-deltaRnH-encoding AdV5 was also used to correct the disease-causing mutation of the phenylalanine hydroxylase (Pah)enu2 allele in phenylketonuria (PKU) mice with an average efficiency of 8% (up to 17.3%), leading to therapeutic reduction of blood phenylalanine (L-Phe) levels. Our study demonstrates in vivo prime editing in the liver with high precision and editing rates sufficient to treat a number of metabolic liver diseases, emphasizing the potential of prime editing for future therapeutic applications.