Dicerna added that the proposed parallel-group, placebo-controlled, Phase 1/2 study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of DCR-A1AT in adult healthy volunteers (HVs) and patients with A1AT
deficiency-associated liver disease.
Caption: Figure 2: Quantitation of hepatic genes: AFP, A1AT
, HNF4a, albumin mRNA levels by RT-qPCR analysis in HLCs, HepG2 (hepatocarcinoma cell line), hepatocytes, and iPSCs.
Long-term prognosis for patients with A1AT
deficiency who present with evidence of liver disease in infancy is reasonably favorable with approximately 80% manifesting no clinical evidence of chronic liver disease when followed into early adulthood .
The majority of the proteins can be categorized as either positive APR reactants (i.e., KNG1, FETA, MBL2, A1AT
, and A2M) or negative APR proteins (i.e., TRFE, ALBU, and APOA1).
The association of MDBs with alcoholic hepatitis was initially reported in 1911.7 Though most commonly attributed to an alcohol-related metabolic insult to the liver, MDBs can also be seen within the hepatocyte cytoplasm in Wilson disease, primary biliary cirrhosis, non-alcoholic steatohepatitis (NASH), alpha-1-antitrypsin (A1AT
) deficiency, porphyria, and morbid obesity.
Enrichment of A1AT
in the six out of eight enriched biological processes by DAVID software in gene set enrichment analysis hints on its important role in pathogenesis of FSGS that can be further investigated.
iPSCs that had undergone ZFN-mediated correction were differentiated in vitro into hepatocyte-like cells (the main cell type affected in the disease) that secreted active A1AT
protein at levels comparable to normal adult hepatocytes.
The paper describes highly specific and efficient ZFN-mediated correction of a defective human A1AT
gene in iPSCs derived from skin cells from individuals with alpha 1-antitrypsin deficiency (A1ATD).
Creatine kinase, amino-S-transferase (AST), alanine transaminase (ALT), LDH, [alpha]l antitrypsin (A1AT
), haptoglobin (HPT), C-reactive protein (CRP), and fibrinogen (FIB) were analyzed in plasma.
. Of the patients tested, 93 out of 105 were of the phenotype M, 12 out of 105 were of the phenotype MS.
Leucocyte counts (including total WBC, neutrophils, bands, and lymphocytes), electrolytes (Na and Ca), enzymes (AP, CPK, and A1AT
), total protein, albumin, globulin, triglycerides, hemoglobin, MCH, MCHC, T4, and T3 were so affected.