作者: Van Zyl, Anel ; Du Plessis, Jan ; Van Heerden, Jaques ; Wouters, Kristien ; Geel, Jennifer ; Van Emmenes, Barry ; Kruger, Mariana ; Büchner, Ané ; Hadley, G. P. ; Hendricks, Marc ; Vermeulen, Johani ; Naidu, Gita

Achieving remission after induction therapy in high-risk neuroblastoma (HR-NB) is of significant prognostic importance. This study investigated remission after induction-chemotherapy using three standard neuroblastoma protocols in the South African (SA) setting. Retrospective data of 261 patients with HR-NB diagnosed between January 2000 and December 2016, who completed induction chemotherapy with standard treatment protocols were evaluated. The treatment protocols were either OPEC/OJEC or the St Jude NB84 protocol (NB84) or rapid COJEC (rCOJEC). The postinduction metastatic complete remission (mCR) rate, 2-year overall survival (OS) and 2-year event free survival (EFS) were determined as comparative denominators. The majority (48.3%; n = 126) received OPEC/OJEC, while 70 patients received (26.8%) rCOJEC and 65 (24.9%) NB84. Treatment with NB84 had the best mCR rate (36.9%), followed by OPEC/OJEC (32.5%) and rCOJEC (21.4%). The 2-year OS of treatment with NB84 was 41% compared to OPEC/OJEC (35%) and rCOJEC (24%) (p = 0.010). The 2-year EFS of treatment with NB84 was 37% compared to OPEC/OJEC (35%) and rCOJEC (18%) (p = 0.008). OPEC/OJEC had the least treatment-related deaths (1.6%) compared to rCOJEC (7.1%) and NB84 (7.5%) (p = 0.037). On multivariate analysis LDH (p = 0.023), ferritin (p = 0.002) and INSS stage (p = 0.006) were identified as significant prognostic factors for OS. The induction chemotherapy was not significant for OS (p = 0.18), but significant for EFS (p = 0.08) Treatment with NB84 achieved better mCR, OS and EFS, while OPEC/OJEC had the least treatment-related deaths. In resource-constrained settings, OPEC/OJEC is advised as induction chemotherapy in HR-NB due to less toxicity as reflected in less treatment-related deaths.

2014-03-01·Molecular Genetics and Metabolism2区 · 生物学

Long-term nonsense suppression therapy moderates MPS I-H disease progression

2区 · 生物学

Article

作者: Gunn, Gwen ; Belakhov, Valery ; Kandasamy, Jeyakumar ; Baasov, Timor ; Schoeb, Trenton R ; Bedwell, David M ; Du, Ming ; Dai, Yanying ; Keeling, Kim M

Nonsense suppression therapy is a therapeutic approach aimed at treating genetic diseases caused by in-frame premature termination codons (PTCs; also commonly known as nonsense mutations). This approach utilizes compounds that suppress translation termination at PTCs, which allows translation to continue and partial levels of deficient protein function to be restored. We hypothesize that suppression therapy can attenuate the lysosomal storage disease mucopolysaccharidosis type I-Hurler (MPS I-H), the severe form of α-L-iduronidase deficiency. α-L-iduronidase participates in glycosaminoglycan (GAG) catabolism and its insufficiency causes progressive GAG accumulation and onset of the MPS I-H phenotype, which consists of multiple somatic and neurological defects. 60-80% of MPS I-H patients carry a nonsense mutation in the IDUA gene. We previously showed that 2-week treatment with the designer aminoglycoside NB84 restored enough α-L-iduronidase function via PTC suppression to reduce tissue GAG accumulation in the Idua(tm1Kmke) MPS I-H mouse model, which carries a PTC homologous to the human IDUA-W402X nonsense mutation. Here we report that long-term NB84 administration maintains α-L-iduronidase activity and GAG reduction in Idua(tm1Kmke) mice throughout a 28-week treatment period. An examination of more complex MPS I-H phenotypes in Idua(tm1Kmke) mice following 28-week NB84 treatment revealed significant moderation of the disease in multiple tissues, including the brain, heart and bone, that are resistant to current MPS I-H therapies. This study represents the first demonstration that long-term nonsense suppression therapy can moderate progression of a genetic disease.

2013-03-01·Journal of Pharmaceutical and Biomedical Analysis3区 · 医学

Development of generic immunoassay for the detection of a series of aminoglycosides with 6′-OH group for the treatment of genetic diseases in biological samples

3区 · 医学

Article

作者: Moran Shalev ; Nir Skalka ; Timor Baasov ; Jeyakumar Kandasamy ; Valery Belakhov ; Rina Rosin-Arbesfeld

Over the last two decades, a growing number of scientific evidences highlighted the potential therapeutic value of several structures of aminoglycoside antibiotics (including gentamicin and G418) for the treatment of various genetic diseases caused by nonsense mutations. These findings resulted in a fast evolvement of synthetic derivatives of aminoglycosides which were shown to be more target specific and less toxic than the clinically used antibiotics. The emerging progress in drug design and development has necessitated the urge to develop a fast, easy and accurate procedure for the determination of these potential therapeutic agents in various biologically derived matrices. Here we describe the preparation of a generic polyclonal antibody that was used for the development of homologous and heterologous immunoassays for the detection of a wide range of natural and synthetic aminoglycoside derivatives, highlighted today as potential therapeutic agents for the treatment of various genetic diseases. A common two-ring scaffold, NB82, present in the majority of compounds exhibiting potent biological activity, was used as a generic immunization hapten for the immunization of two rabbits. By using a series of chemical steps, NB82 was selectively conjugated via the N-1 position through glutaric acid linker to a carrier protein. Sensitivity (I₅₀) values for the recognition of three representative compounds NB82, NB84 and NB124 were determined to be 10 ± 3 ng mL⁻¹, 0.5 ± 0.04 μg mL⁻¹ and 1 ± 0.12 μg mL⁻¹, respectively. Limits of detection were determined to be 1 ± 0.3 ng mL⁻¹ for NB82, 20 ± 7 ng mL⁻¹ for NB84 and 15 ± 8 ng mL⁻¹ for NB124. The developed assays were further exploited for the in vivo monitoring of the therapeutic compounds in mice serum. Serum experimentations exhibited similar detection limits as observed for the PBS calibration experiments, demonstrating no interference with assays sensitivity, with rather high recovery ratios ranging from 92 to 107% in whole blood samples.

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适应症	最高研发状态	国家/地区	公司	日期
莱伯先天性黑蒙	临床2期	美国	Eloxx Pharmaceuticals, Inc.	-
Usher综合征	临床2期	美国	Eloxx Pharmaceuticals, Inc.	-
囊性纤维化	临床前	以色列	Technion-Israel Institute of Technology	2010-06-01
黏多糖贮积症I型	临床前	以色列	Technion-Israel Institute of Technology	2010-06-01
杜氏肌营养不良症	临床前	以色列	Technion-Israel Institute of Technology	2010-06-01