OP45 – 3024: Efficient lentiviral vector-mediated hematopoietic stem cell gene therapy in MNGIE mice

Yadak, Rana; Torres‐Torronteras, Javier; Bogaerts, Elly; Ruijter, George; Barquinero, Jordi; Martí, Ramón; Smeets, Hubert J.M.; Huston, Marshall W.; Til, Niek P. van; Wagemaker, Gerard; Coo, I. F. M. De

doi:10.1016/s1090-3798(15)30046-5

Cited by 4 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…More recently, we developed clinically applicable LVs that carry human TYMP cDNA, and demonstrated long-term biochemical correction in Tymp -/- Upp1 -/- mice at low vector copy number (VCN). Our data demonstrates the feasibility to further develop clinical protocols for HSCGT for MNGIE ( Yadak et al, 2015 ). Similar results in a long-term follow up of 20 months confirms the correction of biochemical imbalances which was maintained at low VCN and chimerism ( Torres-Torronteras et al, 2016 ).…”

Section: Pre-clinical Experimental Approaches Toward Therapymentioning

confidence: 71%

Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

Yadak

Smitt

Gisbergen

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp-/-Upp1-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease.

show abstract

Section: Pre-clinical Experimental Approaches Toward Therapymentioning

confidence: 71%

Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

Yadak

Smitt

Gisbergen

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Еще одним методом лечения лизосомных болезней накопления считается генная терапия ex vivo, при которой проводится трансфекция гена в аутологичные стволовые клетки, которые впоследствии снова вводят пациенту. Лентивирусные векторы в генной терапии ex vivo использовались для экспериментального лечения нескольких генетических заболеваний и показали, что они эффективны для коррекции некоторых дефектов нейронов на моделях мыши с МПС I и IIIA [48,49]. Генетическая терапия лентивирусными векторами ex vivo улучшает биохимические показатели в тканях и уменьшает нарушения центральной нервной системы у мышей с MПС II.…”

Section: генотерапияunclassified

Current Approaches to the Treatment of Hunter Syndrome

et al. 2018

View full text Add to dashboard Cite

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked hereditary disorder associated with a deficiency of iduronate2-sulfatase (IDS). IDS deficiency provokes the accumulation of dermatan sulfate and heparan sulfate in different tissues. Clinical manifestations of MPS II are heterogeneous and involve different organs. Two phenotypes are distinguished: attenuated or severe; classification is based on central nervous system impairment signs. The review provides data on the current treatments opportunities for Hunter syndrome and perspectives for development of new therapeutic approaches. Current treatment includes intravenous enzyme replacement therapy (ERT), hematopoietic stem cell transplantation, and symptomatic treatment. Intravenous enzyme replacement therapy does not promote the enzyme to penetrate the blood-brain barrier which leads to the treatment failure for neurological signs and symptoms; hematopoietic stem cell transplantation has high risk of post-transplantation complications but can improve some neurological problems. Intrathecal ERT, substrate reduction, pharmacological chaperones, and gene therapy are currently under investigation as therapies for severe form of MPS II. Development of new approaches to treatment of Hunter syndrome and other hereditary diseases is extremely vital.

show abstract