Parenti Sachs

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Lysosomal storage disorders LSDs parenti Sachs a group of inborn metabolic diseases caused by mutations in genes that encode proteins involved in different lysosomal functions, in most instances acidic hydrolases. Different therapeutic approaches have been developed to treat these disorders. Pharmacological chaperone therapy PCT is an emerging approach based on small-molecule ligands that selectively bind and stabilize mutant enzymes, increase their cellular levels, and improve lysosomal trafficking and activity.

Parenti Sachs to other approaches, PCT shows advantages, particularly in terms of oral parenti Sachs, broad parenti Sachs, and positive impact on patients' quality of life. After preclinical in vitro and in vivo studies, PCT is now being translated in the first clinical trials, either as monotherapy or in combination with enzyme replacement therapy, for some of the most prevalent LSDs.

For some LSDs, the results of the first clinical trials are encouraging and warrant parenti Sachs development. Future research in the field of PCT will be directed toward the identification of novel chaperones, including new allosteric drugs, and the exploitation of synergies between chaperone treatment and parenti Sachs therapeutic approaches.

Lysosomal storage disorders LSDs represent a heterogeneous group of more than 50 distinct diseases, each of which results from functional deficiency of a particular lysosomal protein.

For the majority of LSDs, the defective protein is a soluble acidic hydrolase, while several others are caused by deficiency of integral membrane, activator, transporter, or nonlysosomal proteins that are necessary for lysosomal function. Severity of clinical manifestations, age at onset, and disease course often vary among individuals with the same LSD, resulting in broad clinical presentation.

In general, LSDs substantially impact patients' health, quality of life, life expectancy, and physical parenti Sachs intellectual performances. While each LSD parenti Sachs quite rare, collectively parenti Sachs affect a large number of individuals, with an estimated incidence rate oftolive births.

Even though LSDs are rare, their biological and clinical interest is high. These diseases represent models to understand lysosomal function and parenti Sachs role in cellular biology.

Furthermore, over the past 25 years, intensive and continuous advancements have been made parenti Sachs develop therapies that are specifically aimed at correcting the metabolic defect s of LSDs. The majority of these therapeutic approaches parenti Sachs directed parenti Sachs increasing the cellular activity or level of parenti Sachs defective enzyme or protein, with the ultimate goal of lowering the accumulated substrate in key cell types and tissues.

Given that the underlying cause of most LSDs is deficiency of a particular enzyme activity, the primary therapeutic approach parenti Sachs has been most successful and broadly reached to date is enzyme replacement therapy ERT.

ERT is based on the periodic intravenous administration of a manufactured enzyme that can be taken up into cells, be parenti Sachs to lysosomes, and reduce substrate storage. Similar to ERT, normal enzyme also may be provided as a precursor that is secreted parenti Sachs the circulation by allograft of transplanted cells hematopoietic stem cell transplantation HSCT 7 or by a patient's own engineered cells.

The balance between protein synthesis, folding, and degradation is a closely monitored and highly dynamic process that is critical to maintain cellular protein homeostasis, i. Parenti Sachs folding of the nascent protein fails despite the action of molecular chaperones, the protein may be recognized by the ER quality control system as aberrant and targeted for degradation either by the lysosome or by the proteasome.

The cellular pathways that control folding of lysosomal enzymes. During synthesis, proteins in this case, lysosomal enzymes or proteins are cotranslationally assisted by molecular chaperones and folding factors e. Upon recognition and binding to the nascent polypeptide, molecular chaperones can stabilize protein conformation, inhibit parenti Sachs misfolding, and prevent aggregation. Enzymes that are correctly folded and stable pass the quality control QC of the endoplasmic reticulum ERexit the ER efficiently, and traffic to parenti Sachs.

In the case of LSDs, the ER quality control often recognizes mutant forms of lysosomal enzymes that retain catalytic activity or that have only modestly compromised function, due to parenti Sachs modifications in their stability or conformation. This recognition may prevent trafficking through the secretory pathway and result in loss of function due to premature degradation or ER aggregation.

Parenti Sachs on an parenti Sachs understanding of these mechanisms, several small-molecule approaches to correct deficiencies that result from mutations in parenti Sachs enzymes have emerged over the past 15 years. Mechanism of action of pharmacological chaperones. Pharmacological chaperones hexagons are small-molecule ligands that selectively bind parenti Sachs stabilize otherwise unstable enzymes and enhance or partially restore their folding and stability.

Enzymes that are rescued by pharmacological chaperones can be normally trafficked, thus increasing residual activity in lysosomes. Lysosomal enzyme synthesis occurs in the neutral pH environment of the ER. As these enzymes are acidic hydrolases, many tend to be thermodynamically less stable at neutral pH compared to the low-pH environment of lysosomes. In this context, pharmacological chaperones selectively bind and stabilize a specific target enzyme, resulting in increased parenti Sachs cellular levels, and passage through the quality control mechanisms of the ER, with subsequent delivery to lysosomes.

While many types of mutations have been identified in LSDs, including large deletions, insertions, premature stop codons, and splicing mutations, missense mutations tend to be more common. For most LSDs, it has been speculated that substrate storage occurs if residual enzyme activity falls below a certain threshold Figure 3 and that above a certain level, accumulation of clinically relevant quantities of substrate would require a duration that exceeds the human life span.

Correlations between residual activity and LSD phenotype. For most LSDs, correlations have been observed between residual enzyme activity and disease severity.

It has been speculated that substrate storage occurs if residual activity falls below a certain threshold. LSD, lysosomal storage disorder. While some of the underlying pathologies and affected organ systems are treated well by ERT, others are not. This is often due to poor tissue access, as well parenti Sachs inefficient cellular uptake and lysosomal delivery. In particular, the ability to target the central nervous system has not been achieved, given the inability of large proteins to cross the blood—brain barrier.

In principle, PCT has the potential to address at least parenti Sachs of the limitations of existing therapies. Pharmacological chaperones are small molecules with published data indicating, as a class, good oral bioavailability, broad tissue distribution to key cell types and tissues including the brain, and the ability to diffuse across membranes, achieving therapeutic concentrations in specific cellular compartments.

Enhancement of enzyme activity by PCT also may lead to sustained and stable enzyme levels, more closely mimicking the natural production of these endogenous parenti Sachs as compared to weekly or biweekly ERT administration that leads parenti Sachs intermittent and fluctuating cellular activity. In addition, unlike the manufactured enzymes used for ERT, pharmacological chaperones are nonimmunogenic and would not be expected to have tolerability issues parenti Sachs to those described for a number of different ERTs.

In fact, the safety profiles of some pharmacological chaperones have been evaluated clinically and appear to be acceptable. Table 1 provides a list of selected chaperones that have shown the greatest potential for clinical studies.

PCT has also been proposed as a potential therapy for Gaucher disease. These molecules can be parenti Sachs as carbohydrate mimetics iminosugars, azasugars, and carbasugars or noncarbohydrate compounds identified by high-throughput screening initiatives. IFG is an azasugar that binds both wild-type and mutant forms of GCase, resulting in stabilization and increased cellular and lysosomal levels, 4950 particularly for the NS variant.

In the LP and NS models, IFG administration resulted in reduced liver and spleen weights, providing evidence of in vivo efficacy. In parenti Sachs VL model, which to some extent mimics neuronopathic forms of the disease, increases in GCase protein levels and activity in brain, reduced neuroinflammation, delayed onset of neurological disease, and increased life spans were demonstrated. Ambroxol, an approved expectorant, was identified from a screen of 1, Food and Drug Administration—approved drugs by parenti Sachs ability to stabilize wild-type GCase against thermal denaturation.

Deficiency in GAA activity results in generalized glycogen accumulation in heart, skeletal muscle, and other tissues. However, ERT shows limitations, particularly in terms of restricted bioavailability, insufficient correction of disease pathology in some muscles, tolerability issues, and immunogenicity.

Small-molecule chaperones have been proposed as a potential alternative to ERT for the treatment of Pompe disease. Although PCT has several potential advantages over existing therapies and parenti Sachs already shown clinical efficacy in one LSD i. In parenti Sachs cases, chaperones are reversible competitive inhibitors of target enzymes.

To date, most pharmacological chaperones that have been identified bind to the active site of their target enzyme, thus acting as inhibitors. Initially, the idea of using small-molecule, active-site inhibitors to increase total cellular enzyme activity was counterintuitive. However, in many cases, if used appropriately, net gains in in situ lysosomal activity and reduced substrate levels can be realized.

In addition, once delivered to the lysosome, high concentrations of accumulated substrate can compete with the chaperone for binding to the target enzyme, thus facilitating substrate turnover rather than enzyme inhibition. Increases in residual activity may be too low for significant benefit. Preclinical studies have shown variable increases in activity in the presence of chaperones. While some enzyme variants appear to respond quite well, others show only minor net increases in activity i. For some diseases and for some specific mutations, parenti Sachs enhancement in residual activity obtained with PCT may not be sufficient to translate into significant benefit for patients, particularly if tissue pathology is already fully established.

However, insufficient correction of the enzymatic defect and pathology in specific tissues is also a challenge with ERT and other approaches see above.

Only a fraction of mutations are responsive to chaperone therapy. Not all LSD patients have missense mutations and not all missense mutations are responsive to chaperones.

The determinants of chaperone response have been analyzed and depend both on the type of mutation and on the specific chaperone molecule tested. Molecules that interact with different domains of the protein including noncatalytic domains may have the potential to expand the spectrum of responsive parenti Sachs. The rate of responsive mutations parenti Sachs in the different LSDs. Interestingly, in some cases, endogenous wild-type parenti Sachs also show a response to chaperones, while in other instances, they do not.

For example, DNJ enhances wild-type Gaa in mice and rats very robustly, but less so in monkeys; virtually no enhancement of wild-type GAA was seen in white blood cells WBCs of healthy human volunteers unpublished results. As mentioned above, how well the chaperone interacts and coordinates key amino acid side chains to confer parenti Sachs stability may also play a role.

Different strategies have been devised to address the potential limitations of pharmacological chaperones. The parenti Sachs half-life of the target enzyme typically days parenti Sachs to that of the pharmacological chaperone typically hours can be used to develop optimal dose and administration regimens that allow maximal substrate turnover, thereby addressing parenti Sachs on potential inhibition. Current research is focused on the identification of pharmacological chaperones that bind allosteric sites of target enzymes.

The stabilization mechanism of these allosteric compounds would be, in principle, similar to the active site-directed compounds and require a sufficient binding affinity to increase the stability of the mutant enzyme structure. However, allosteric chaperones would have the additional advantage that they can remain bound to parenti Sachs enzyme during catalysis without risk of inhibition.

Examples of allosteric pharmacological chaperones are now being parenti Sachs. A high-throughput screen of more thancompounds identified 1- 3,4-dimethoxybenzyl propylthioxo-2,3,5,6,7,8-hexahydropyrimido[4,5-d]pyrimidin-4 1H -one ML Although PCT has been designed to rescue endogenous mutant misfolded proteins, studies suggest that chaperones are able to increase the stability of the wild-type enzymes that are commonly used for Parenti Sachs.

This effect has the potential to translate into enhanced efficacy of ERT and to address some of the limitations of chaperones. In cultured fibroblasts from Parenti Sachs patients, coincubation of the chaperone NB-DNJ with rhGAA ERT resulted in greater correction of enzyme activity and increased amounts of the recombinant enzyme in lysosomal compartments.

Thus, in principle, this approach may be beneficial to any patient on ERT, if treated with the specific chaperone. In addition, the administration of the chaperone could be restricted only to the time of ERT infusions, thus reducing parenti Sachs risk of any potentially undesired events that may be related to the chronic use of the chaperone.

After preclinical studies, pharmacological chaperone research is in a phase of parenti Sachs translation, parenti Sachs five chaperones for four LSDs now evaluated in clinical studies, parenti Sachs others showing promise Table 1. Galactose was the first pharmacological chaperone investigated for Fabry disease. DGJ, the active component of the investigational parenti Sachs migalastat hydrochloride Amicus Therapeutics, Cranbury, NJ is being developed as a treatment for Fabry disease.

Across all phase 2 studies, migalastat was generally safe and well tolerated. To date, data presented parenti Sachs scientific conferences have shown the efficacy of migalastat in stabilizing renal function, reducing left ventricular mass, and improving gastrointestinal symptoms in Fabry disease patients with amenable mutations. Long-term open-label extension studies of migalastat are parenti Sachs.

As discussed, two pharmacological chaperones have advanced to the clinic as potential therapies for Gaucher disease: IFG and Ambroxol. In phase 1 studies, IFG showed dose-related elevations of up to parenti Sachs. Subsequently, two phase 2 studies were initiated. As expected for parenti Sachs short-term study, disease markers including platelet, hemoglobin, glucosylceramide, and chitotriosidase levels were unchanged.