New treatment strategies for lysosomal storage disorders

سال انتشار: 1398
نوع سند: مقاله کنفرانسی
زبان: انگلیسی
مشاهده: 447

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شناسه ملی سند علمی:

GDRC12_020

تاریخ نمایه سازی: 5 بهمن 1398

چکیده مقاله:

introduction: lysosomal storage disorders (LSD) are a heterogenic group of more than 60 rare inborn errors of inherited metabolic disorders(1), While collectively they have an estimated total incidence of about 1:7.500 (1 in 4000-8000) and are relalively frequent, but individually the LSDS are rare with incidences ranging from 1:5700 (Gaucher disease) to 1:4.200.000 (sialidosis)(2).The clinical manifestations are broad and progressive with premature death in most patients (3).Up to now about 16 orphan drugs are approved for 11 different LSDS. Established treatments include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT). Substrate reduction therapy (SRT), and chaperon therapy (CT), but generally treatments for LSDS are mainly directed to relieving symptoms of disease by supportive medical therapies (3).Available treatment strategies have some limitations such as immunological reactions and a limited effect on organs such as bones, muscles and brain. There for new treatment options are in development include either in preclinical trials in animal models or in affected patients in clinical phase 1-3 trials. These new treatments may directly target gene mutations, mutant enzymes, the deficient lysosomal enzyme activity, substrate storage or secondry cell abnormalities (4).ERT have major limitations:1: the large size of the delivered recombinant enzymes do not diffuse easily into all affected tissues such as bone, cartilage and skeletal muscle.2: It has low capacity to ameliorate neurological manifestatios because it cannot cross the blood-brain barrier (5).Also as enzyme replacement therapies are only approved for a limited of LSDS , there is a sustained need to develop new ERTS, first for not yet treatable LSDS and second because a need for an improved organ delivery or ERTS which need to overcome the blood- Brain barrier. Within the last decade the number of treatable LSDS has markably increased and are now being developed for previously untreatable ultra-rare LSDS such as MPS type VII or for α - manosidosis. But because of limitations of ERT discussed sooner, second generations ERTS are being developed with change in structure to improve the cellular uptake or by binding to fusion proteins. Examples of this enzyme are for fabry disease and pompe disease New treatments approaches try to overcome the blood-brain barrier, either by intrathecal (IT) or by intracerebroventricular (ICV) application of enzyme or by IV application of fusion proteins which are able to pass the blood brain barrier by receptor- mediated transcytosis. Samples of these new enzymes are for MPS II, MPS IIIA, NCL2, MPS IIIB and MPS I (6, 7).The second strategy is chaperone therapy. Missense mutation often lead to misfolding and subsequent impairment of lysosomal trafficking as well as instability of mutant lysosomal enzyme. Misfiled proteins are usually recognized by the endoplasmic reliculum quality control followed by proteosomal degradation. Pharmacological chaperones are small molecules that help misfolded mutant proteins to be folded and routed correctly within the cell. There are three categories of small molecular weight compounds that have been described, the first are PCs that are usually inhibitory molecules that stabilize misfolded proteins by increasing their cellular levels (8). The second class are chemical chaperones such as glycerol. These group are unspecific molecules that unlike PCs alter the surrounding glycerol conditions (8).The third class of low molecular weight compound are proteostasis regulator (PRS) that increase proteostasis network functional capacity (9). The use of chaperones in treatment of LSDs has been proposed due to the limitation of ERT and other conventation therapies, because PCS, unlike ERT, have a broad tissue availability including the brain (10). migalastat is an oral pharmacologic chaperone, which stabilizes specific mutant forms of α-galactosidase and increase enzyme trafficking to lysosomes. It was found to be safe and well tolerated (11, 12).The third option for treatment of LSDs is gene therapy. Trials on gene therapy focus primarily on the brain disease. Four essential problems, are the route of vector application, the selection of vectors leading to most efficient enzyme production, immunological reactions to vector and enzyme and duration of gene expression. Based on the results of different animal models, phase 1-2 gene therapy trials have been performed in a little patients with MPS IIIA, MPS IIIB (13). Today, intravascular gene therapies are in preparation for patients with none neurological LSDS. This method leading to a sustained expression up to an entire life time thus presumably making continuous ERT unnecessary (5).Another mode of treatment in LSDs is cyclodextrin therapy. Cyclodextrin is a cyclic oligosaccharide that extensively employed as a pharmaceutical excipient and in animal models is used for Neiman-pick C treatment with good results (14).However, the limitation is that this application must be intrathecal or intracerbroventricular and also hearing impairment seems to be an important side effect of this treatment (14). The last treatment option is anti-inflammatory treatment because it has been elucidated that secondary phenomena such as inflammation process play an important role in the phatophysiology of LSDS (15).So in animal models, treatment with pentosan polysulfat and TNF-α-antagonists are started (15). In MPS I and MPS II concerning bone and joint disease first promising result have been reported (16, 17).