DISEASE DIAGNOSIS/ THERAPY

Disease Diagnosis/ Therapy

Disease Diagnosis/ Therapy

Section 1

Introduction

Gene therapy has begun to achieve the success that many had predicted (Aiuti et al., 2002). Clinical results of studies in severe combined immunodeficiency (SCID), Fanconi anemia (FA) and hemophilia B accumulated a body of positive responses to gene transfer.

The lysosomal storage disorders (LSDs) are a subset of inborn errors of metabolism. As such, they are caused by the deficiency of a specific gene product, which in most cases is an enzyme involved in the catabolic pathway of macromolecular structures. The concept that each protein is the product of a single gene, proposed by Garrod in 1908, followed by the studies of Beadle and Tatum in 1941, originated the one gene-one enzyme hypothesis, which is the basic concept used for current gene therapy in the inborn errors of metabolism and especially in the LSDs (Ballard, 2008, 56).

The lysosomal membrane contains several specific carriers for the transport of solutes across the membrane. Most of these substrates are the products from the enzymatic degradation of macromolecules (single amino acids, dipeptides, monosaccharides and lipids), but some specific carriers also transport vitamins, heavy metals and drugs (Mancini et al., 2000).

Although more than 20 carriers have been characterized, only four genes have been identified. The gene CTNS encodes cystinosin, the transporter that is defective in nephropathic cystinosis, a lysosomal storage disease caused by the intralysosomal storage of cystine crystals. The gene SLC17A5 (solute carrier family 17, onion/sugar transporter, member 5) encodes sialin, the sialic acid transporter that is defective in sialic acid storage disease.

The gene NPC1 encodes a novel type of human permease and is mutated in individuals with Niemann-Pick disease type CI. The fourth gene, LYAAT-1 (MIM 606561), encodes lysosomal amino acid transporter 1, which transports small neutral amino acids such as alanine, proline and ?-amino butyric acid (GABA), and has been identified as a member of the eukaryotic specific amino acids/auxin permease (AAAP) family but is not coupled to a human disease. Despite the amount of different advances, a major inconvenience has been encountered in treatment of SCID by current gene transfer strategies. Two cases of T cell leukemia have been reported to date in a group of patients who had received gene therapy using retroviral vectors. Such events have been directly related to the retroviral-mediated insertion of the gene product into the LMO-2 oncogene, which is responsible for childhood leukemia. This issue raises concern about insertional mutagenesis for the development of new gene therapy trials based on the use of retroviral vectors (Bruneau, 2009, 258)

LSDs caused by enzyme deficiency

The majority of the LSDs fit into this major pathophysiological group. These diseases are caused by the deficiency of one enzyme responsible for the catabolism or degradation of a macromolecule (Cabrera-Salazar et al., 2002). These degradative processes are required to dispose of the debris of cell turnover. Failure to breakdown these materials results in their accumulation in the lysosome, which produces cell dysfunction and, in some cases, cell ...