Innovative Treatments for Lysosomal Diseases

Cox, Timothy M.

doi:10.1016/j.beem.2015.01.001

Cited by 24 publications

(21 citation statements)

References 166 publications

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“…Phase I studies assessed safety, tolerability and pharmacokinetics in escalating single and multiple doses [ 68 ] and, soon after their results were released and clinical safety of the compound demonstrated, an open-label, single arm phase II clinical trial was initiated [ 61 , 65 ]. The results of both studies were published in detail and, overall, they showed that eliglustat tartrate was safe and effective: in healthy volunteers, plasma GCase concentrations were decreased after oral dosing with the drug and, in open-label phase II clinical trials in patients with GD1, impressive hematological responses were detected together with significant decreases in spleen and liver volumes [ 69 , 70 , 71 , 72 , 73 ]. In general, the primary outcomes of organ size reduction and improvements in hematological parameters were either comparable or exceeded those observed with imiglucerase, while clearly exceeding those reported for miglustat.…”

Section: From Concept To Clinicsmentioning

confidence: 99%

Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

Coutinho

Santos

Alves

2016

IJMS

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Lysosomal storage diseases (LSDs) are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, efforts have been mainly targeting the functional loss of the enzyme, by injection of a recombinant formulation, in a process called enzyme replacement therapy (ERT), with no impact on neuropathology. This ineffectiveness, together with its high cost and lifelong dependence is amongst the main reasons why additional therapeutic approaches are being (and have to be) investigated: chaperone therapy; gene enhancement; gene therapy; and, alternatively, substrate reduction therapy (SRT), whose aim is to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the levels of biosynthesis of the accumulating substrate(s). Here we review the concept of substrate reduction, highlighting the major breakthroughs in the field and discussing the future of SRT, not only as a monotherapy but also, especially, as complementary approach for LSDs.

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Section: From Concept To Clinicsmentioning

confidence: 99%

Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

Coutinho

Santos

Alves

2016

IJMS

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“…ERT is safer than HSCT, but expensive, requires lifelong periodic infusions, and does not effectively treat LSDs with neuronopathic symptoms. Hence, other therapies are under evaluation [9,13,14]. These include gene enhancement, gene therapy [15], chaperone therapy, and substrate reduction therapy [16].…”

Section: Therapiesmentioning

confidence: 99%

“…These include gene enhancement, gene therapy [15], chaperone therapy, and substrate reduction therapy [16]. More recently, combination therapies, such as HSCT/ERT or HSCT/gene therapy, have been under investigation [13,14]. Since newborn screening offers an opportunity for early diagnosis, the cohort of newborns affected with LSDs detected by screening will expand and the development of better therapies will be accelerated.…”

Section: Therapiesmentioning

confidence: 99%

Newborn Screening for Krabbe Disease and Other Lysosomal Storage Disorders: Broad Lessons Learned

Orsini

Casini

2017

IJNS

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Newborn screening (NBS) for Krabbe disease (KD) began in New York (NY) in August 2006. In summary, after eight years of screening there were five infants identified with early-onset Krabbe disease. Four underwent transplant, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. An additional forty-six asymptomatic infants were found to be at moderate or high risk for disease. Screening for KD is both analytically and medically challenging; since screening for KD possesses both of these challenges, and many more, the lessons learned thus far could be used to predict the challenges that may be faced when screening for other lysosomal storage disorders (LSDs). This paper briefly reviews reports of NBS for LSDs from varied world programs. The challenges encountered in screening for KD in NY will be highlighted, and this experience, combined with hindsight, will inform what may be expected in the future as screening for LSDs expands.

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“…One of possible options is the use of small molecules, able to cross the blood-brain-barrier, which could impair synthesis of GAGs. This strategy is called substrate reduction therapy [3]. It was demonstrated that genistein (5, 7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) inhibited GAG A C C E P T E D M A N U S C R I P T…”

Section: Introductionmentioning

confidence: 99%

“…Although there are intensive studies on various therapies for MPS, and enzyme replacement therapy has already been introduced for some types of this disease (MPS I, II, IVA, and VI), there is still a need for development of novel, effective treatment procedures, especially to manage the dysfunction of central nervous system [3]. One of possible options is the use of small molecules, able to cross the blood-brain-barrier, which could impair synthesis of GAGs.…”

Section: Introductionmentioning

confidence: 99%

Cell cycle is disturbed in mucopolysaccharidosis type II fibroblasts, and can be improved by genistein

Moskot

Gabig-Cimińska

Jakóbkiewicz‐Banecka

et al. 2016

Gene

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Mucopolysaccharidoses (MPSs) are inherited metabolic diseases caused by mutations resulting in deficiency of one of enzymes involved in degradation of glycosaminoglycans (GAGs). These compounds accumulate in cells causing their dysfunctions. Genistein is a molecule previously found to both modify GAG metabolism and modulate cell cycle. Therefore, we investigated whether the cell cycle is affected in MPS cells and if genistein can influence this process. Fibroblasts derived from patients suffering from MPS types I, II, IIIA and IIIB, as well as normal human fibroblasts (the HDFa cell line) were investigated. MTT assay was used for determination of cell proliferation, and the cell cycle was analyzed by using the MUSE® Cell Analyzer. While effects of genistein on cell proliferation were similar in both normal and MPS fibroblasts, fractions of cells in the G0/G1 phase were higher, and number of cells entering the S and G2/M phases was considerably lower in MPS II fibroblasts relative to control cells. Somewhat similar tendency, though significantly less pronounced, could be noted in MPS I, but only at longer times of incubation. However, this was not observed in MPS IIIA and MPS IIIB fibroblasts. Genistein (5, 7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) was found to be able to partially correct the disturbances in the MPS II cell cycle, and to some extent in MPS I, at higher concentrations of this compound. The tendency to increase the fractions of cells entering the S and G2/M phases was also observed in MPS IIIA and IIIB fibroblasts treated with genistein. In conclusion, this is the first report indicating that the cell cycle can be impaired in MPS cells. The finding that genistein can improve the MPS II (and to some extent also MPS I) cell cycle provides an input to our knowledge on the molecular mechanisms of action of this compound.

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Innovative Treatments for Lysosomal Diseases

Cited by 24 publications

References 166 publications

Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

Newborn Screening for Krabbe Disease and Other Lysosomal Storage Disorders: Broad Lessons Learned

Cell cycle is disturbed in mucopolysaccharidosis type II fibroblasts, and can be improved by genistein

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