Current Pharmaceutical Design - Volume 17, Issue 24, 2011

Successful liver-directed gene therapy has the potential to revolutionize medicine. Helper-dependent adenoviral vectors (HDAds) are devoid of all viral coding sequences and have shown tremendous potential for liver-direct gene therapy. In small and large animals, hepatic transduction with HDAd has resulted in high level, long-term transgene expression without chronic toxicity in a variety of disease models. Recent advance Read More

Gene therapy holds great promise for the treatment of inherited metabolic disease. Among different vector systems used to date, vectors based on adeno-associated virus (AAV) have shown great potential for systemic expression of therapeutic transgenes. The main advantages of AAV are the beneficial safety profile and the possibility to generate long-term transgene expression without the necessity for chromosomal integrati Read More

Retroviral vectors have been used for several decades for the transfer of therapeutic genes to various cells or organs including the liver. Initial studies aimed at treating inherited liver deficiencies were carried out with murine oncoretroviral vectors either delivered directly to the organ or using an ex vivo strategy that entailed harvest of the hepatocytes, transduction during a culture phase and further reinfusion to the pati Read More

The liver acts as a host to many functions hence raising the possibility that any one may be compromised by a single gene defect. Inherited or de novo mutations in these genes may result in relatively mild diseases or be so devastating that death within the first weeks or months of life is inevitable. Some diseases can be managed using conventional medicines whereas others are, as yet, untreatable. In this review we con Read More

Hepatocytes are a key target for gene transfer directed at correction of inborn errors of metabolism. The theoretical potential of hepatocyte-directed gene transfer contrasts with the hurdles for clinical translation of this technology. Innate immune responses following gene transfer are initiated by recognition of pathogen-associated molecular patterns by pattern recognition receptors like Toll-like receptors. Adaptive im Read More

There are numerous inborn errors of metabolism of the liver, and they are all rare to very rare. To get a clear picture of the indications for gene transfer in these conditions, it is essential to get a clear view on the current (lack of) insight in the pathophysiology of these disorders, the current treatment options and hence on the window of opportunity for new treatments as gene transfer. The aim of this review, is to illustrate th Read More

Lysosomal Storage Diseases (LSDs) comprise a group of over fifty inherited metabolic disorders, with their hallmark feature being deficient catabolism and accumulation (storage) of macromolecules in the lysosomes due to genetic deficiency of specific lysosomal enzymes. The combined incidence of LSDs is estimated to be ∼1 in 7,000 births. LSD symptoms can vary significantly, primarily due to the nature of th Read More

Familial hypercholesterolemia (FH) is an inherited metabolic disorder characterized by high levels of plasma low density lipoproteins (LDL) and an increased risk of premature atherosclerosis and coronary heart disease. LDL receptor (LDLr) deficiency is the most prevalent cause of FH. Therefore, hepatocyte-directed LDLr gene transfer constitutes an important strategy for the treatment of this monogenetic disease. No Read More