scholarly journals Innovative Treatments for Mucopolysaccharidoses

2018 ◽  
Vol 08 (01) ◽  
pp. e163-e171
Author(s):  
Florian Lagler
Keyword(s):  
Small Molecules ◽  
Drug Distribution ◽  
Enzyme Concentration ◽  
Hematopoietic Stem ◽  
Immune Reactions ◽  
Encapsulated Cells ◽  
Enzyme Replacement ◽  
Emerging Therapies ◽  
Therapeutic Molecules ◽  
Causal Treatment

AbstractMucopolysaccharidoses (MPSs) are caused by deficiency of specific lysosomal enzymes that affect the degradation of mucopolysaccharides or glycosaminoglycans. Since more than 15 years enzyme replacement therapies are available for an increasing number of MPSs. These therapies together with hematopoietic stem cell transplantation today are the gold standard of causal treatment in MPS. Despite confirmed efficacy, both do not cure these severe conditions. In this article, we discuss the limitations of established and promises of emerging therapies. The limitations of intravenous enzyme replacement and cell therapy can be summarized as immune reactions against the therapeutic molecules/cells and the failure to restore enduring and sufficient enzyme concentration in all relevant tissues. Accordingly, innovative approaches comprise small molecules and encapsulated cells that do not activate antitherapeutic immune reactions, several gene therapy approaches that aim for sustained enzyme expression, and new enzymes that penetrate blood–brain and other barriers for drug distribution. This article provides an update on the state of development of these new therapies and highlights enduring challenges.

Therapeutic Options for Mucopolysaccharidosis II (Hunter Disease)

2020 ◽  
Vol 26 (40) ◽  
pp. 5100-5109
Author(s):  
Francyne Kubaski ◽  
Filippo Vairo ◽  
Guilherme Baldo ◽  
Fabiano de Oliveira Poswar ◽  
Amauri Dalla Corte ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Small Molecules ◽  
Genome Editing ◽  
Fusion Proteins ◽  
Therapeutic Options ◽  
Hematopoietic Stem ◽  
Hunter Disease ◽  
Enzyme Replacement ◽  
Mps Ii ◽  
The Impact

Background: Mucopolysaccharidosis type II (Hunter syndrome, or MPS II) is an X-linked lysosomal disorder caused by the deficiency of iduronate-2-sulfatase, which leads to the accumulation of glycosaminoglycans (GAGs) in a variety of tissues, resulting in a multisystemic disease that can also impair the central nervous system (CNS). Objective: This review focuses on providing the latest information and expert opinion about the therapies available and under development for MPS II. Methods: We have comprehensively revised the latest studies about hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT - intravenous, intrathecal, intracerebroventricular, and intravenous with fusion proteins), small molecules, gene therapy/genome editing, and supportive management. Results and Discussion: Intravenous ERT is a well-established specific therapy, which ameliorates the somatic features but not the CNS manifestations. Intrathecal or intracerebroventricular ERT and intravenous ERT with fusion proteins, presently under development, seem to be able to reduce the levels of GAGs in the CNS and have the potential of reducing the impact of the neurological burden of the disease. Gene therapy and/or genome editing have shown promising results in preclinical studies, bringing hope for a “one-time therapy” soon. Results with HSCT in MPS II are controversial, and small molecules could potentially address some disease manifestations. In addition to the specific therapeutic options, supportive care plays a major role in the management of these patients. Conclusion: At this time, the treatment of individuals with MPS II is mainly based on intravenous ERT, whereas HSCT can be a potential alternative in specific cases. In the coming years, several new therapy options that target the neurological phenotype of MPS II should be available.

scholarly journals Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jane E. Potter ◽  
Gemma Petts ◽  
Arunabha Ghosh ◽  
Fiona J. White ◽  
Jane L. Kinsella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Multimodal Therapy ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Venous Access ◽  
Cell Transplant ◽  
New Paradigm ◽  
Hematopoietic Stem ◽  
Wolman Disease ◽  
Enzyme Replacement

Abstract Background Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access. Results We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT—multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition. Conclusion We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.

scholarly journals Anderson–Fabry Disease: From Endothelial Dysfunction to Emerging Therapies

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Cosimo A. Stamerra ◽  
Rita Del Pinto ◽  
Paolo di Giosia ◽  
Claudio Ferri ◽  
Amirhossein Sahebkar
Keyword(s):  
Fabry Disease ◽  
Organ Damage ◽  
Lysosomal Storage ◽  
Messenger Ribonucleic Acid ◽  
Gene Therapies ◽  
Enzyme Replacement ◽  
Emerging Therapies ◽  
Life Threatening ◽  
Molecular Aspects ◽  
Partial Deficiency

The Anderson–Fabry disease is a rare, X-linked, multisystemic, progressive lysosomal storage disease caused by α-galactosidase A total or partial deficiency. The resulting syndrome is mainly characterized by early-onset autonomic neuropathy and life-threatening multiorgan involvement, including renal insufficiency, heart disease, and early stroke. The enzyme deficiency leads to tissue accumulation of the glycosphingolipid globotriaosylceramide and its analogues, but the mechanisms linking such accumulation to organ damage are only partially understood. In contrast, enzyme replacement and chaperone therapies are already fully available to patients and allow substantial amelioration of quality and quantity of life. Substrate reduction, messenger ribonucleic acid (mRNA)-based, and gene therapies are also on the horizon. In this review, the clinical scenario and molecular aspects of Anderson–Fabry disease are described, along with updates on disease mechanisms and emerging therapies.

scholarly journals GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

2020 ◽  
Vol 21 (17) ◽  
pp. 6213
Author(s):  
Andrés Felipe Leal ◽  
Eliana Benincore-Flórez ◽  
Daniela Solano-Galarza ◽  
Rafael Guillermo Garzón Jaramillo ◽  
Olga Yaneth Echeverri-Peña ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protein Transport ◽  
Current Knowledge ◽  
Sandhoff Disease ◽  
Substrate Reduction Therapy ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Central Nervous System Dysfunction ◽  
Gm2 Gangliosidoses

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency

Blood ◽  
2009 ◽  
Vol 114 (15) ◽  
pp. 3216-3226 ◽  
Author(s):  
Aisha V. Sauer ◽  
Emanuela Mrak ◽  
Raisa Jofra Hernandez ◽  
Elena Zacchi ◽  
Francesco Cavani ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Severe Combined Immunodeficiency ◽  
Intrinsic Defect ◽  
Combined Immunodeficiency ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Bone Phenotype

Abstract Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin axis, causing decreased osteoclastogenesis and an intrinsic defect of osteoblast function with subsequent low bone formation. In vitro, osteoblasts lacking ADA displayed an altered transcriptional profile and growth reduction. Furthermore, the bone marrow microenvironment of ADA-deficient mice showed a reduced capacity to support in vitro and in vivo hematopoiesis. Treatment of ADA-deficient neonatal mice with enzyme replacement therapy, bone marrow transplantation, or gene therapy resulted in full recovery of the altered bone parameters. Remarkably, untreated ADA–severe combined immunodeficiency patients showed a similar imbalance in RANKL/osteoprotegerin levels alongside severe growth retardation. Gene therapy with ADA-transduced hematopoietic stem cells increased serum RANKL levels and children's growth. Our results indicate that the ADA metabolism represents a crucial modulatory factor of bone cell activities and remodeling. The trials were registered at www.clinicaltrials.gov as #NCT00598481 and #NCT00599781.

Long-Term and Sustained Correction of the α-Galactosidase A Deficiency in Fabry Mice and Patient Cells Receiving Lentivirally Transduced Hematopoietic Stem/Progenitor Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1285-1285
Author(s):  
Makoto Yoshimitsu ◽  
Christopher Siatskas ◽  
Sheng-Ben Liang ◽  
Vanessa I. Rasaiah ◽  
Koji Higuchi ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Stable Gene ◽  
Inherited Disorders ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
Enzyme Replacement ◽  
Vector Systems

Abstract Fabry disease is a lysosomal storage disease caused by a defect in α-galactosidase A (α-gal A). Currently enzyme replacement therapy is available; however frequent infusions are required and long-term outcome in key organs remain to be established. Stable gene augmentation by virus-based delivery can correct cells and offers considerable potential as an effective, long-term therapeutic approach. Our goal is to engineer life-long correction of the disorder with a single treatment. Transplantation of genetically modified autologous hematopoietic stem/progenitor cells (HSPCs), which can self-renew and differentiate multiple cell types, is thus an attractive target in this context. Previously we have demonstrated long-term correction mediated by gene transfer into HSPCs by oncoretroviral vectors both with pre-selection of transduced cells prior to transplantation and without. In the interest of minimizing the effect on the graft by reducing ex vivo culture time and possibly reducing deleterious integration events, we are pursuing other integrative vector systems. It is well known that recombinant lentiviral vectors (LVs) can efficiently transduce not only dividing cells but also non-dividing or less-cycling cells like HSPCs. The aim of this study is to evaluate whether VSV-g pseudotyped LV-mediated gene modification of HSPCs can systemically treat affected organs in Fabry disease mouse model (Fabry mice). We first demonstrated sustained LV-mediated marking of peripheral blood (PB) cells by transducing bone marrow mononuclear cells (BMMNCs) with an LV which encodes enGFP cDNA at an MOI of 30 and transplanting into Fabry mice. Stable and robust enGFP expression (n=5, 65.8±5.8%) in PB cells was observed for >250 days. Next, we transplanted Fabry mice with BMMNCs transduced with an LV encoding the human α-gal A cDNA. Sustained expression of functional α-gal A in Fabry mice was observed over 24 weeks. Plasma α-gal A activity from treated Fabry mice (n=9) was two-fold higher than wild-type controls (n=8). Increased α-gal A activity, often above normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed including heart and kidney which are life-threatening in Fabry disease. To determine whether true HPSCs were transduced by LVs, secondary BM transplantations were performed. PB from secondary transplanted Fabry mice showed multilineage enGFP marking of PB, splenocytes, and BMMNCs, along with therapeutic levels of α-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34+ cells from a Fabry patient with corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease. These studies provide confirmation of the utility of this system for research and therapy for a variety of inherited disorders including Fabry disease.

Small Molecule Combination Enhances CD34+/CD38- Cell Proliferation Via Inhibition of Differentiation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 658-658
Author(s):  
Lan Wang ◽  
Xin Guan ◽  
Huihui Wang ◽  
Bin Shen ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Small Molecules ◽  
Cell Expansion ◽  
Target Genes ◽  
Ex Vivo ◽  
Hematopoietic Stem ◽  
Qpcr Analysis ◽  
Cd34 Cells ◽  
Cells Cultured

Abstract Hematopoietic stem cells (HSCs) have become increasingly attractive for the therapy of various hematological system disorders. The aim of this study is to identify approaches that promote the expansion of HSCs. We present here the identification of a combination of small molecules and cytokines that is effective in retaining high stemness of hematopoietic stem/progenitor cells while promoting cell proliferation by inhibiting differentiation. Firstly, five small-molecule candidates were screened for their individual effects on ex vivo expansion of human peripheral blood CD34+ cells in the presence of selected cytokines. The best compounds at their optimal concentrations were further analyzed in combination, to achieve maximum capacity for stimulating the CD34+CD38- cell expansion ex vivo. The extent of cell expansion and the immunophenotype of expanded cells were assessed through flow cytometry. Additional cell and molecular assays were performed to confirm that the expanded CD34± cells are functionally normal in vitro. Subsequently, the expanded cells were transplanted into sublethally irradiated NOD/SCID mice for the assessment ofhuman cell viability and engraftment potential in vivo. Furthermore, the expression of several genes in the cell proliferation and differentiation pathways was analyzed through qPCR during the process of CD34±cell expansion. Following multiple rounds of screening, an optimal formula (named as "SVC cocktail") was obtained, which consisted of four cytokines (stem cell factor, flt-3 ligand, thrombopoietin and interleukin-6) and three small molecules (Stem Regenin 1, valproic acid and CAY10433). CD34+ cells cultured with SVC cocktail had a purity of 76.2%±7.5% and reached expansion folds of 27.9±4.3 for CD34+/CD38- HSCs on day 7. In contrast, CD34+ cells cultured with the cytokines alone displayed a purity of 27.4%±6.3% and expansion folds of 15.5±2.2 for CD34+/CD38- cells. The groups with small molecules only (plus DMSO, the vehicle), or with basal medium only, showed no surviving cells on day 4. Furthermore, cell cycle analysis indicated that the SVC cocktail-induced CD34+/CD38- cells stayed in a more quiescent state (G0/G1: 75.2%±3.6%; S: 9.2%±2.4%). On the other hand, the cells cultured without the three small molecules had active DNA synthesis (G0/G1: 56.0%±2.0%; S: 31.8%±3.2%), implicating a trend of enhanced cell differentiation in the cytokine alone group. RT-qPCR analysis further demonstrated that the expression of HSC stemness markers CD90, CD133, CD117, ALDH1, Bmi1, HoxB4, GATA-2, Runx1, and CXCR4 were elevated in the SVC cocktail-induced CD34+ cells, but dramatically reduced or barely detectable in the cytokine alone group. In addition, CFU assays for the SVC cocktail group vs the cytokine alone group demonstrated BFU-E of 54.0±4.6 vs 11.7±1.5, CFU-GM of 71.0±2.7 vs 8.3±2.5, CFU-GEMM of 40.7±3.8 vs 5.0±2.0 and CFU-Mk of 6.7±1.5 vs 0.7±0.6, respectively. For the in vivo engraftment in mouse bone marrow, human CD45 rate in the SVC cocktail group was much higher than in the cytokine alone group (21.1%±2.7% vs 0.5%±0.1%); similar group differences were also found in the CD34+ and CD34+CD38- rate (7.7%±1.4% vs 1.6%±1.2% and 6.8%±2.2% vs 1.6%±0.1% respectively), all at 8 weeks post transplantation. Moreover, qPCR analysis of Notch and Wnt signaling pathways for cultured cells on day 7 showed that the expression of Notch target genes (related to high activation of HSC property) was enhanced in the SVC cocktail group compare to the cytokine group (HES5: 9.2±2.3 vs 3.6±1.4 in arbitrary units; HEY1: 6.3±1.9 vs 2.6±1.2; HES1: 3.2±1.3 vs 1.3±0.4; Notch1: 1.4±0.3 vs 1.2±0.3), whereas the expression of Wnt target genes (related to activation of HSC differentiation) was greater in the cytokine alone group than in the SVC cocktail group (CCND1: 10.1±4.3 vs 1.2±0.8; LEF1: 4.3±0.6 vs 2.9±0.2; PPAR D: 3.4±0.3 vs 1.5±0.1; FZD2: 1.8±0.2 vs 1.0±0.1). Taken together, our results show that the new SVC cocktail is able to retain the characteristics of HSCs remarkably well, by enhancing their expansion while inhibiting their differentiation. Mechanistically, it appears that the three small molecules can effectively inhibit the cytokines' pro-differentiation effects on CD34+CD38- cells without affecting the cytokines' ability to stimulate cell proliferation. Disclosures Wang: Biopharmagen Corp.: Employment. Ren:Biopharmagen Corp: Employment. Jiang:Biopharmagen Corp: Consultancy.

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