There has recently been rapid progress in understanding receptors that generate intracellular signals from inositol lipids. One of these lipids, phosphatidylinositol 4,5-bisphosphate, is hydrolysed to diacylglycerol and inositol trisphosphate as part of a signal transduction mechanism for controlling a variety of cellular processes including secretion, metabolism, phototransduction and cell proliferation. Diacylglycerol operates within the plane of the membrane to activate protein kinase C, whereas inositol trisphosphate is released into the cytoplasm to function as a second messenger for mobilizing intracellular calcium.

Inositol trisphosphate, a novel second messenger in cellular signal transduction.

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1053/jhep.2003.50346

A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.21178

Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection

Receptor-effector coupling by G proteins

AGA technical review on nonalcoholic fatty liver disease

Regulation of adenylate cyclase of human platelet membranes by forskolin.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840040517

Serum Activity of Mitochondrial Aspartate Aminotransferase: A Sensitive Marker of Alcoholism With or Without Alcoholic Hepatitis

Hepatic alpha 1-adrenergic receptors show agonist-specific regulation by guanine nucleotides. Loss of nucleotide effect after adrenalectomy.

Effective Inhibition of HBV Replication in Vivo by Anti-HBx Short Hairpin RNAs

Objective

A defect of the lysosomal enzyme α-L-iduronidase (IDUA) interrupts the degradation of glycosaminoglycans in mucopolysaccharidosis type I, causing severe neurological manifestations in children with Hurler's syndrome. Delivery of the missing enzyme through stereotactic injection of adeno-associated virus vectors coding for IDUA prevents neuropathology in affected mice. We examined the efficacy and the safety of this approach in enzyme-deficient dogs.



Methods

Because deficient dogs raise antibodies against IDUA in response to infusion, intracerebral vector injections were combined with an immunosuppressive regimen.



Results

Treatment was tolerated well. We observed broad dispersion of vector genomes in the brain of efficiently immunosuppressed dogs. The delivery of IDUA to large areas, which could encompass the entire brain, prevented glycosaminoglycan and secondary ganglioside accumulations. This condition was associated with drastic reduction of neuropathology throughout the encephalon. In contrast, vector injection combined with partial immunosuppression was associated with subacute encephalitis, production of antibodies against IDUA in brain tissues, and elimination of genetically modified cells.



Interpretation

Gene therapy directed to the entire brain is feasible and may be beneficial to children with Hurler's syndrome. The possibility of subacute encephalitis emphasizes the importance of preventing immune response against IDUA, a problem that needs to be considered in similar therapies for other genetic defects. Ann Neurol 2006;

Nicolas Ferry

Papers

Regulation of adenylate cyclase of human platelet membranes by forskolin.

Serum Activity of Mitochondrial Aspartate Aminotransferase: A Sensitive Marker of Alcoholism With or Without Alcoholic Hepatitis

Hepatic alpha 1-adrenergic receptors show agonist-specific regulation by guanine nucleotides. Loss of nucleotide effect after adrenalectomy.

Effective Inhibition of HBV Replication in Vivo by Anti-HBx Short Hairpin RNAs

Gene therapy of the brain in the dog model of Hurler's syndrome.