Accumulation Of Macromolecules Research Articles

Intracellular dry mass density increases under growth-induced pressure

Cells that proliferate in confined environments develop mechanical compressive stress, referred to as growth-induced pressure, which inhibits growth and division across various organisms. Recent studies have shown that in these confined spaces, the diffusivity of intracellular nanoparticles decreases. However, the physical mechanisms behind this reduction remain unclear. In this study, we use quantitative phase imaging to measure the refractive index and dry mass density of Saccharomyces cerevisiae cells proliferating under confinement in a microfluidic bioreactor. Our results indicate that the observed decrease in diffusivity can be at least attributed to the intracellular accumulation of macromolecules. Furthermore, the linear scaling between cell content and growth-induced pressure suggests that the concentrations of macromolecules and osmolytes are maintained proportionally under such pressure in S. cerevisiae.

Managing the interactions of illumination, nitrogen, and sodium bicarbonate for autotrophic biomass production and macromolecules accumulation in the microalga Chlorella sorokiniana

Understanding how cultivation variables holistically impact microalgal biomass production and macromolecule accumulation is essential toward sustainable scaling-up in open ponds. Efficient, non-wasteful resource utilization is imperative. This study examines the effects of three factors —illumination intensity, nitrogen loading, and inorganic carbon loading (as NaHCO3)—on Chlorella sorokiniana autotrophic cultures. By employing a Taguchi L9 design, these factors were evaluated, while let varying across three levels each. Illumination has the most significant effect on biomass production, while nitrogen loading inversely affected protein and carbohydrate content. No factor appeared significant for lipid accumulation, hinting that carbohydrate biosynthesis might overshadow lipid production. Using the derived statistical model, optimal conditions for maximizing biomass were determined: 7500 lx illumination, 250 mg NaNO3 L−1, and 750 mg NaHCO3 L−1, resulting in a biomass yield of 1105 mg L−1 in 16 days, with a robust R-squared (pred) value of 95.85 %. The obtained insight supports sustainable microalgal biomass production.

Localized Increased Permeability of Blood-Brain Barrier for Antibody Conjugates in the Cuprizone Model of Demyelination.

The development of new neurotherapeutics depends on appropriate animal models being chosen in preclinical studies. The cuprizone model is an effective tool for studying demyelination and remyelination processes in the brain, but blood-brain barrier (BBB) integrity in the cuprizone model is still a topic for debate. Several publications claim that the BBB remains intact during cuprizone-induced demyelination; others demonstrate results that could explain the increased BBB permeability. In this study, we aim to analyze the permeability of the BBB for different macromolecules, particularly antibody conjugates, in a cuprizone-induced model of demyelination. We compared the traditional approach using Evans blue injection with subsequent dye extraction and detection of antibody conjugates using magnetic resonance imaging (MRI) and confocal microscopy to analyze BBB permeability in the cuprizone model. First, we validated our model of demyelination by performing T2-weighted MRI, diffusion tensor imaging, quantitative rt-PCR to detect changes in mRNA expression of myelin basic protein and proteolipid protein, and Luxol fast blue histological staining of myelin. Intraperitoneal injection of Evans blue did not result in any differences between the fluorescent signal in the brain of healthy and cuprizone-treated mice (IVIS analysis with subsequent dye extraction). In contrast, intravenous injection of antibody conjugates (anti-GFAP or non-specific IgG) after 4 weeks of a cuprizone diet demonstrated accumulation in the corpus callosum of cuprizone-treated mice both by contrast-enhanced MRI (for gadolinium-labeled antibodies) and by fluorescence microscopy (for Alexa488-labeled antibodies). Our results suggest that the methods with better sensitivity could detect the accumulation of macromolecules (such as fluorescent-labeled or gadolinium-labeled antibody conjugates) in the brain, suggesting a local BBB disruption in the demyelinating area. These findings support previous investigations that questioned BBB integrity in the cuprizone model and demonstrate the possibility of delivering antibody conjugates to the corpus callosum of cuprizone-treated mice.

Tire-Derived Transformation Product 6PPD-Quinone Induces Mortality and Transcriptionally Disrupts Vascular Permeability Pathways in Developing Coho Salmon.

Urban stormwater runoff frequently contains the car tire transformation product 6PPD-quinone, which is highly toxic to juvenile and adult coho salmon (Onchorychus kisutch). However, it is currently unclear if embryonic stages are impacted. We addressed this by exposing developing coho salmon embryos starting at the eyed stage to three concentrations of 6PPD-quinone twice weekly until hatch. Impacts on survival and growth were assessed. Further, whole-transcriptome sequencing was performed on recently hatched alevin to address the potential mechanism of 6PPD-quinone-induced toxicity. Acute mortality was not elicited in developing coho salmon embryos at environmentally measured concentrations lethal to juveniles and adults, however, growth was inhibited. Immediately after hatching, coho salmon were sensitive to 6PPD-quinone mortality, implicating a large window of juvenile vulnerability prior to smoltification. Molecularly, 6PPD-quinone induced dose-dependent effects that implicated broad dysregulation of genomic pathways governing cell-cell contacts and endothelial permeability. These pathways are consistent with previous observations of macromolecule accumulation in the brains of coho salmon exposed to 6PPD-quinone, implicating blood-brain barrier disruption as a potential pathway for toxicity. Overall, our data suggests that developing coho salmon exposed to 6PPD-quinone are at risk for adverse health events upon hatching while indicating potential mechanism(s) of action for this highly toxic chemical.

Elephantiasis nostras verrucosa: case report

Lymphedema is a clinical condition in which an accumulation of macromolecules occurs in the interstitial space and an atypical evolution known as elephantiasis nostras verrucosa may occur. The objective of this study is to report on the clinical evolution and analysis of the progression of a 56-year-old patient with a diagnosis of primary bilateral stage II lymphoedema. With an atypical presentation of it, identified as elephantiasis nostra verrucosa. The patient had suffered from lymphoestatic edema since he was 10 years old, having previously received ineffective treatments until he arrived at the Clinica Godoy in Sao Jose de Rio Preto Brazil, where he underwent an intensive therapy procedure treatment model proposed by Godoy and Godoy; in which favorable results were obtained in a short period of time. Lymphedema is a chronic disease that is manageable but not curable. It is also difficult to be treated, especially if it has progressed to a late stage such as elephantiasis nostras verrucosa associated the continuous and repetitive infectious and inflammatory processes over time must have contributed to the evolution of the fibrotic pattern. Intensive treatment based on the Godoy method® is possible reduce in short period of time the volume and improve fibrosis and quality of life this patient.

Ocean warming and acidification affect the transitional C:N:P ratio and macromolecular accumulation in the harmful raphidophyte Heterosigma akashiwo

Despite an increase in ocean warming and acidification that is expected to increase the number of harmful algal species worldwide, the population of the raphidophyte Heterosigma akashiwo has been reported to be reduced. However, how this species physically and metabolically modifies transitional C:N:P ratio and macromolecule accumulation is unknown. Considering 1st, 10th, and 20th culture generations under present (low-temperature; low-carbon-dioxide [LTLC] 21 °C; pCO2 400 ppm) and future (high-temperature; high-carbon-dioxide [HTHC] 25 °C; pCO2 1000 ppm) ocean conditions, we examined transitional C:N:P ratio and macromolecule level changes and performed transcriptome sequencing. The results showed that compared to 1st generation cells, 20th generation cells under HTHC conditions showed a large decrease in carbon quota (QC: 34%), nitrogen quota (QN: 36%), and phosphorus quota (QP: 32%), which were reflected in an overall reduction in DNA and RNA quantity. Decreased activation of photosynthetic, carbon fixation and lipid metabolic pathways coincided with changes in photosynthetic efficiency, carbon concentration, and lipid accumulation after long-term (20th generation) exposure to HTHC conditions. We observed that these variations in internal metabolic pathways were caused by external changes in temperature, which activated the (Ca+) signaling pathway, and external changes in pCO2, which altered proton exchange pathways. Our results suggest that H. akashiwo in a temperate environment will undergo profound changes in C:N:P ratio and macromolecular properties, leading to programmed cell death, in the future.

Control of nuclear size by osmotic forces in Schizosaccharomyces pombe.

The size of the nucleus scales robustly with cell size so that the nuclear-to-cell volume ratio (N/C ratio) is maintained during cell growth in many cell types. The mechanism responsible for this scaling remains mysterious. Previous studies have established that the N/C ratio is not determined by DNA amount but is instead influenced by factors such as nuclear envelope mechanics and nuclear transport. Here, we developed a quantitative model for nuclear size control based upon colloid osmotic pressure and tested key predictions in the fission yeast Schizosaccharomyces pombe. This model posits that the N/C ratio is determined by the numbers of macromolecules in the nucleoplasm and cytoplasm. Osmotic shift experiments showed that the fission yeast nucleus behaves as an ideal osmometer whose volume is primarily dictated by osmotic forces. Inhibition of nuclear export caused accumulation of macromolecules in the nucleoplasm, leading to nuclear swelling. We further demonstrated that the N/C ratio is maintained by a homeostasis mechanism based upon synthesis of macromolecules during growth. These studies demonstrate the functions of colloid osmotic pressure in intracellular organization and size control.

Effects of CO2 concentration and light intensity on macromolecules accumulation of Micractinium sp.

Economically efficient biomass production is crucial to lift the microalgal circular bioeconomy requiring low production cost with higher biomass and value-added products. In this study, Micractinium sp. YACCYB505 was cultured at different illuminations (1600, 2400, 3200 lux) and CO2 conditions (up to 10%) to evaluate biomass productivity and accumulation of macromolecules (lipid, carbohydrate and protein). The product optimization study was conducted to analyze individual variables of environmental factors by using a Box-Behnken design. Highlight intensity (3200 lux) and 5% CO2 aeration maximized biomass productivity on 11th day of microalgal harvest. Microalgal lipid accumulation indicated positive impact on increased CO2 aeration and light intensity treatment. Similarly, a considerable amount of protein content (9%) was increased at higher CO2 aeration but raised light intensity had a negative impact on protein biosynthesis. Significant carbohydrate content reduction was observed with increased light intensity and CO2 aeration. The overall results proved that increased CO2 concentration (10%) and light intensity (3200 lux) enhanced lipid accumulation (32%) and biomass productivity in Micractinium sp., which provides potential to achieve a sustainable, cost-effective biomass and value-added products.

Abstract 1574: LSD-germline variant drive oncogenicity

Abstract Lysosome storage disease (LSD) is a congenital metabolic disorder caused by mutations in genes involved in the function of lysosomes. Defects in the genes encoding hydrolases and transporters and enzyme activators are found in LSD’s, leading to the accumulation of macromolecules in the late endocytic system. And this disruption of lysosomal homeostasis increases the induction of endoplasmic reticulum and oxidative stress, proliferative signal transduction, extracellular matrix degradation, Integrin-β4-mediated cell migration and invasion, and consequently can promote the development of oncogenic cells and malignant tumors. It is known that the function of lysosomes is very important in cancer diseases. Recently, through a preliminary study, we found that the incidence of myeloproliferative neoplasm (MPN) increases statistically significantly when the LSD putative pathogenic germline variant (PPGV) is present. Based on this, we performed single-cell RNA (scRNA) sequencing using MPN patient samples of both LSD PPGV carrier and non-carrier. We tried to determine how the LSD PPGV affects MPN cancer progression at the single-cell level. To confirm functional differences between the two groups, DEG, pathway enrichment, LR-pair interaction, and transcription enrichment analyses were performed. In the analysis, immune cells were composed of T-cell, NK-cell, and Monocyte (in the order of frequency). It was confirmed that Lysosome-related (ER, Golgi, etc.) functions were upregulated in the carrier group compared to the non-carrier group across cell types. In addition, in the ligand-receptor (LR)-pair interaction analysis targeting Immune cells, it was possible to find a statistically significant difference (average log2 fold change>0.7 and p-value<0.05) candidate LR-pair (IL6-IL6R*IL6ST) that upregulates in the carrier group compared to the non-carrier group. The candidate LR-pair found by our team has been previously known as a cytokine-related gene that plays an inflammatory or fibrosis-related role in MPN and affects cancer progression. Also, in the Transcription Factor Enrichment analysis conducted together, it was confirmed that the statistically significant (NES>2 and FDR<0.01) candidate Transcription Factor (STAT1), which operates dependent on the candidate LR-pair, is upregulated. In conclusion, we found the possibility that genes and functions related to cancer progression can be up-regulated by LSD germline variants. In addition, we plan to conduct additional studies to determine the exact mechanism of contribution to cancer development by the LSD germline variant. Citation Format: Hyundong Yoon, Seulki Song, Yeeun Ha, Youngil Koh, SungSoo Yoon. LSD-germline variant drive oncogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1574.

Mass spectrometry-based proteomics in neurodegenerative lysosomal storage disorders.

The major function of the lysosome is to degrade unwanted materials such as lipids, proteins, and nucleic acids; therefore, deficits of the lysosomal system can result in improper degradation and trafficking of these biomolecules. Diseases associated with lysosomal failure can be lethal and are termed lysosomal storage disorders (LSDs), which affect 1 in 5000 live births collectively. LSDs are inherited metabolic diseases caused by mutations in single lysosomal and non-lysosomal proteins and resulting in the subsequent accumulation of macromolecules within. Most LSD patients present with neurodegenerative clinical symptoms, as well as damage in other organs. The discovery of new biomarkers is necessary to understand and monitor these diseases and to track therapeutic progress. Over the past ten years, mass spectrometry (MS)-based proteomics has flourished in the biomarker studies in many diseases, including neurodegenerative, and more specifically, LSDs. In this review, biomarkers of disease pathophysiology and monitoring of LSDs revealed by MS-based proteomics are discussed, including examples from Niemann-Pick disease type C, Fabry disease, neuronal ceroid-lipofuscinoses, mucopolysaccharidosis, Krabbe disease, mucolipidosis, and Gaucher disease.

Acoustic Cluster Therapy (ACT®) enhances accumulation of polymeric micelles in the murine brain

The restrictive nature of the blood-brain barrier (BBB) prevents efficient treatment of many brain diseases. Focused ultrasound in combination with microbubbles has shown to safely and transiently increase BBB permeability. Here, the potential of Acoustic Cluster Therapy (ACT®), a microbubble platform specifically engineered for theranostic purposes, to increase the permeability of the BBB and improve accumulation of IRDye® 800CW-PEG and core-crosslinked polymeric micelles (CCPM) in the murine brain, was studied. Contrast enhanced magnetic resonance imaging (MRI) showed increased BBB permeability in all animals after ACT®. Near infrared fluorescence (NIRF) images of excised brains 1 h post ACT® revealed an increased accumulation of the IRDye® 800CW-PEG (5.2-fold) and CCPM (3.7-fold) in ACT®-treated brains compared to control brains, which was retained up to 24 h post ACT®. Confocal laser scanning microscopy (CLSM) showed improved extravasation and penetration of CCPM into the brain parenchyma after ACT®. Histological examination of brain sections showed no treatment related tissue damage. This study demonstrated that ACT® increases the permeability of the BBB and enhances accumulation of macromolecules and clinically relevant nanoparticles to the brain, taking a principal step in enabling improved treatment of various brain diseases.

Using non-metric multi-dimensional scaling analysis and multi-objective optimization to evaluate green algae for production of proteins, carbohydrates, lipids, and simultaneously fix carbon dioxide

Eight green-algae species were investigated to elucidate the effects of growth phases on biomass productivity (CO2 fixation rate) and accumulation of algal macromolecules (proteins, carbohydrates, and lipids). Non-metric multi-dimensional scaling (NMDS) and multiple-objective optimization were applied to evaluate the effects of algal species and growth phases on biomass productivity and algal macromolecule accumulation. Algal species and growth phases had significant impacts on biomass production and composition. NMDS delineated that biomass productivity and protein accumulation of all species were dominant in the log phase, while the stationary phase was favorable for lipid and carbohydrate accumulation. Among the eight algal species, Chlorella vulgaris had the highest biomass productivity (75 mg/L/day) and a high protein content in the exponential phase (53%). Scenedesmus obliquus had the highest protein content (55%) in the log phase, Botryococcus braunii showed the highest lipid content (40%) in the stationary phase, and Staurastrum sp. presented the highest carbohydrate content (37%) in the stationary phase. Two-objective optimization for algal biomass productivity and composition led to the conclusion that Chlorella vulgaris, Botryococcus braunii, and Coelastrum microporum are the preferred strains for accumulation of proteins, lipids, and carbohydrates, respectively, along with good CO2 fixation (biomass productivity). NMDS and multi-objective optimization are useful tools to select preferred strains and corresponding culture conditions from a large pool of candidates for simultaneous biomass and macromolecule accumulation.

Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link?

SummaryThe recent definition of a network of lymphatic vessels in the meninges surrounding the brain and the spinal cord has advanced our knowledge on the functional anatomy of fluid movement within the central nervous system (CNS). Meningeal lymphatic vessels along dural sinuses and main nerves contribute to cerebrospinal fluid (CSF) drainage, integrating the cerebrovascular and periventricular routes, and forming a circuit that we here define as the CNS‐lymphatic unit. The latter unit is important for parenchymal waste clearance, brain homeostasis, and the regulation of immune or inflammatory processes within the brain. Disruption of fluid drain mechanisms may promote or sustain CNS disease, conceivably applicable to epilepsy where extracellular accumulation of macromolecules and metabolic by‐products occur in the interstitial and perivascular spaces. Herein we address an emerging concept and propose a theoretical framework on: (a) how a defect of brain clearance of macromolecules could favor neuronal hyperexcitability and seizures, and (b) whether meningeal lymphatic vessel dysfunction contributes to the neuroimmune cross‐talk in epileptic pathophysiology. We propose possible molecular interventions targeting meningeal lymphatic dysfunctions, a potential target for immune‐mediated epilepsy.

Clinical-Therapeutic Importance of Bioimpedance in Patients with Lymphedema: A Systematic Review

Introduction: Lymphedema is characterized by abnormal accumulation of macromolecules and soft tissue fluids. Bioimpedance is a method that measures intra- and extracellular volumes by body segment, and has been currently used in lymphedema. Objective: The objective of this study was to conduct a systematic review of the clinical-therapeutic importance of bioimpedance in patients with lymphedema. Methodology: The present work consisted of a literature review. The systematic review made it possible to know and transcribe important subjects on clinical and therapeutic bioimpedance in patients with lymphedema. The work was carried out from September 2018 to April 2019, following the rules of systematic review – PRISMA. Results: It was found that the variation of the interstitial fluid can be measured by bioimpedance , before and after intensive treatment of lymphedema. Bioimpedance is a noninvasive method used to evaluate interstitial fluids, including indications for lymphedema. Conclusion: Bioimpedance is a suggested method to evaluate clinical and therapeutic follow-up in patients with lymphedema.

Stromal barriers to nanomedicine penetration in the pancreatic tumor microenvironment.

Pancreatic cancer is known for its dismal prognosis despite efforts to improve therapeutic outcome. Recently, cancer nanomedicine, application of nanotechnology to cancer diagnosis and treatment, has gained interest for treatment of pancreatic cancer. The enhanced permeability and retention (EPR) effect that promotes selective accumulation of nanometer‐sized molecules within tumors is the theoretical rationale of treatment. However, it is clear that EPR may be insufficient in pancreatic cancer as a result of stromal barriers within the tumor microenvironment (TME). These limit intratumoral accumulation of macromolecules. The TME and stromal barriers inside it consist of various stromal cell types which interact both with each other and with tumor cells. We are only beginning to understand the complexities of the stromal barriers within the TME and its functional consequences for nanomedicine. Understanding the complex crosstalk between barrier stromal cells is challenging because of the difficulty of modeling pancreatic cancer TME. Here we provide an overview of stromal barriers within the TME. We also describe the preclinical models, both in vivo and in vitro, developed to study them. We furthermore discuss the critical gaps in our understanding, and how we might formulate a better strategy for using nanomedicine against pancreatic cancer.

The oocyte-to-embryo transition in mouse: past, present, and future.

The oocyte-to-embryo transition (OET) arguably initiates with formation of a primordial follicle and culminates with reprogramming of gene expression during the course of zygotic genome activation. This transition results in converting a highly differentiated cell, i.e. oocyte, to undifferentiated cells, i.e. initial blastomeres of a preimplantation embryo. A plethora of changes occur during the OET and include, but are not limited to, changes in transcription, chromatin structure, and protein synthesis; accumulation of macromolecules and organelles that will comprise the oocyte's maternal contribution to the early embryo; sequential acquisition of meiotic and developmental competence to name but a few. This review will focus on transcriptional and post-transcriptional changes that occur during OET in mouse because such changes are likely the major driving force for OET. We often take a historical and personal perspective, and highlight how advances in experimental methods often catalyzed conceptual advances in understanding the molecular bases for OET. We also point out questions that remain open and therefore represent topics of interest for future investigation.

Non-invasive in vivo Imaging Grading of Liver Fibrosis.

Liver fibrosis (LF), a common consequence of chronic liver diseases with various etiologies, is characterized by excessive accumulation of macromolecules, including collagen, glycoproteins and proteoglycans, in the liver. LF can result in hepatic dysfunction, cirrhosis, portal hypertension and, in some cases, hepatocellular carcinoma. As the current gold standard for diagnosing LF, liver biopsy, however, is invasive and prone to sampling errors and procedure-related complications. Therefore, developing noninvasive, precise and reproducible imaging tests for diagnosing and staging LF is of great significance. Conventional ultrasound (US), computed tomography (CT) and magnetic resonance (MR) imaging can depict morphological alterations of advanced LF, but have relatively limited capability characterizing early-stage LF. In order to optimize the diagnostic performances of noninvasive imaging techniques for LF across its entire spectrum of severity, a number of novel methods, including US elastography, CT perfusion imaging and various MR imaging–based techniques, have been established and introduced to clinical practice. In this review, we intended to summarize current noninvasive imaging techniques for LF, with special emphasis on the possible roles, advantages and limitations of the new emerging imaging modalities.

R1ρ dispersion and sodium imaging in human calf muscle

PurposeTo evaluate the magnitude of chemical exchange effects and R1ρ dispersion in muscle and their relationship to tissue sodium levels with aging. MethodsSeven healthy volunteers (aged 24 to 87years, median age 47) underwent MRI to assess tissue sodium levels and water T1ρ values at different spin-locking frequencies in calf muscles. T1ρ values at each locking field were computed based on a three-parameter mono-exponential model to fit signals obtained at different locking times, and R1ρ (=1/T1ρ) rates were compared at different locking fields. In particular, the dispersion of R1ρ (ΔR1ρ=R1ρ(0Hz)−R1ρ(500Hz)) was examined as a function of subject age. Muscle sodium content was calculated by comparing signal intensities between tissues and reference standards within the same image. The variations of ΔR1ρ with age and sodium were analyzed by linear regression. ResultsT1ρ values and sodium content both increased with age. R1ρ dispersion also increased with age and showed a strong linear correlation (correlation coefficient r=0.98, P=0.000578) with sodium content. ConclusionΔR1ρ reports on the contribution of labile protons such as hydroxyls which may be associated with macromolecule accumulation in the extracellular matrix (ECM). An increase of sodium signal suggests an enlarged ECM volume fraction and/or an increase in sodium concentration, which occurs during normal aging. The strong correlation between ΔR1ρ and sodium is likely the consequence of increased ECM and density of total charged sites within the matrix from molecules such as collagens and proteoglycans. The results from this study show the potential use of R1ρ dispersion and sodium imaging in the assessment of pathological changes in muscle such as fibrosis.

Anesthetic Management of a 13-Year-Old Adolescent With Mucolipidosis Type II for Total Hip Arthroplasty

Mucolipidosis II (ML II) or inclusion cell disease is a rare lysosomal storage disorder, inherited as an autosomal recessive trait. Deficiency of the lysosomal transport enzyme, N-acetylglucosamine-1-phosphotransferease, results in the intracellular accumulation of macromolecules (mucopolysaccharides and mucolipids) in the lysosome which leads to cellular dysfunction and a multi-system disorder. Manifestations are present at birth including muscle hypotonia, a weak cry, and failure to thrive. Additional physical signs include hip dislocation, inguinal hernia, hepatomegaly, limitation of joint movement, and cutaneous changes. Coarse facial features and skeletal abnormalities become more conspicuous with time. A rapidly progressive psychomotor deterioration, developmental delay and growth failure are often noted with a limited life span of 10 years. Due to the aforementioned physical abnormalities, surgical and anesthetic care may be required. We present a 13-year-old girl with ML II who required anesthetic care for a total hip arthroplasty due to chronic right hip dislocation. Previous reports of anesthetic care for these patients are reviewed, end-organ involvement is discussed, and options for anesthetic care are presented. J Med Cases. 2017;8(7):203-206 doi: https://doi.org/10.14740/jmc2834w

Disease models for the development of therapies for lysosomal storage diseases.

Lysosomal storage diseases (LSDs) are a group of rare diseases in which the function of the lysosome is disrupted by the accumulation of macromolecules. The complexity underlying the pathogenesis of LSDs and the small, often pediatric, population of patients make the development of therapies for these diseases challenging. Current treatments are only available for a small subset of LSDs and have not been effective at treating neurological symptoms. Disease-relevant cellular and animal models with high clinical predictability are critical for the discovery and development of new treatments for LSDs. In this paper, we review how LSD patient primary cells and induced pluripotent stem cell-derived cellular models are providing novel assay systems in which phenotypes are more similar to those of the human LSD physiology. Furthermore, larger animal disease models are providing additional tools for evaluation of the efficacy of drug candidates. Early predictors of efficacy and better understanding of disease biology can significantly affect the translational process by focusing efforts on those therapies with the higher probability of success, thus decreasing overall time and cost spent in clinical development and increasing the overall positive outcomes in clinical trials.