Safety & Efficacy of Prolonged Physiologic Erythropoietin (EPO) Level Treatment of Anemia in End Stage Renal Disease (ESRD) Patients Undergoing Peritoneal Dialysis (PD)Using MDGN201 TARGTEPO

The objectives of this study are to assess safety and to evaluate the biologic activity of TARGTEPO treatment in Peritoneal Dialysis patients

Start Date01 Apr 2015

Sponsor / Collaborator

Aevi Genomic Medicine, Inc.

[+1]

NCT02117427 / CompletedPhase 1/2

Safety and Efficacy of Sustained Erythropoietin Therapy of Anemia in Chronic Kidney Disease (CKD) Patients and End-Stage Renal Disease (ESRD) Dialysis Patients Using MDGN201 TARGTEPO

The objectives of this study are to assess safety and to evaluate the biologic activity of TARGTEPO treatment.

Start Date27 May 2014

Sponsor / Collaborator

Aevi Genomic Medicine, Inc.

[+1]

100 Clinical Results associated with Medgenics Medical (Israel) Ltd.

0 Patents (Medical) associated with Medgenics Medical (Israel) Ltd.

Literatures (Medical) associated with Medgenics Medical (Israel) Ltd.

22 Oct 2020·BloodQ1 · MEDICINE

Correcting β-thalassemia by combined therapies that restrict iron and modulate erythropoietin activity

Q1 · MEDICINE

Article

Author: Olivari, Violante ; Nai, Antonella ; Domev, Hagit ; Aghajan, Mariam ; Guo, Shuling ; Di Modica, Simona Maria ; Miari, Reem ; Lidonnici, Maria Rosa ; Shapir, Nir ; Liu, Alison ; Casu, Carla ; Pettinato, Mariateresa ; Lo Presti, Vania ; Munoz, Kevin A. ; Sitara, Despina ; Neil, Garry ; Booten, Sheri ; Zafir-Lavie, Inbal ; Ferrari, Giuliana ; O’Hara, Emir ; Rivella, Stefano

Abstractβ-Thalassemia intermedia is a disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly, and systemic iron overload. Novel approaches are being explored based on the modulation of pathways that reduce iron absorption (ie, using hepcidin activators like Tmprss6-antisense oligonucleotides [ASOs]) or increase erythropoiesis (by erythropoietin [EPO] administration or modulating the ability of transferrin receptor 2 [Tfr2] to control red blood cell [RBC] synthesis). Targeting Tmprss6 messenger RNA by Tmprss6-ASO was proven to be effective in improving IE and splenomegaly by inducing iron restriction. However, we postulated that combinatorial strategies might be superior to single therapies. Here, we combined Tmprss6-ASO with EPO administration or removal of a single Tfr2 allele in the bone marrow of animals affected by β-thalassemia intermedia (Hbbth3/+). EPO administration alone or removal of a single Tfr2 allele increased hemoglobin levels and RBCs. However, EPO or Tfr2 single-allele deletion alone, respectively, exacerbated or did not improve splenomegaly in β-thalassemic mice. To overcome this issue, we postulated that some level of iron restriction (by targeting Tmprss6) would improve splenomegaly while preserving the beneficial effects on RBC production mediated by EPO or Tfr2 deletion. While administration of Tmprss6-ASO alone improved the anemia, the combination of Tmprss6-ASO + EPO or Tmprss6-ASO + Tfr2 single-allele deletion produced significantly higher hemoglobin levels and reduced splenomegaly. In conclusion, our results clearly indicate that these combinatorial approaches are superior to single treatments in ameliorating IE and anemia in β-thalassemia and could provide guidance to translate some of these approaches into viable therapies.

01 Dec 2018·Journal of Controlled ReleaseQ1 · MEDICINE

Successful intracranial delivery of trastuzumab by gene-therapy for treatment of HER2-positive breast cancer brain metastases

Q1 · MEDICINE

Article

Author: Yeini, Eilam ; Krispel, Simi ; Miari, Reem ; Goltsman, Haim ; Satchi-Fainaro, Ronit ; Panet, Amos ; Tal, Osnat ; Neil, Garry A ; Liran, Atar ; Sherbo, Shay ; Benhar, Itai ; Zafir-Lavie, Inbal ; Badinter, Felix ; Shatil, Tamar ; Ofek, Paula ; Shapir, Nir

BACKGROUNDTrastuzumab is a monoclonal antibody which demonstrates efficacy for HER2 positive breast cancer patients. Recently, an increased incidence of brain metastasis in trastuzumab-treated patients has been reported. The reason for this may be the effectiveness of systemic trastuzumab allowing patients to survive longer thus providing time for brain metastases to develop, along with the lack of penetration of systemic therapies through the blood brain barrier. In recent years, several administration routes to the brain have been evaluated. Albeit advances in the field, there is still a need for improved delivery of therapeutic antibodies to the brain. To address this challenge, we have developed two gene therapy-based methods enabling continuous secretion of active trastuzumab in the brain.METHODSWe have developed two gene therapy approaches for the delivery of the therapeutic anti-HER2 monoclonal antibody, trastuzumab, to the brain. We utilized the helper dependent adenovirus vector, containing trastuzumab light and heavy chains coding sequences (HDAd-trastuzumab). In the first approach, we used the Transduced Autologous Restorative Gene Therapy (TARGT) platform, in which dermal fibroblasts of human and mouse origin, are ex-vivo transduced with HDAd-trastuzumab vector, rendering continuous secretion of active trastuzumab from the cells locally. These genetically engineered cells were subsequently implanted intracranially to mice, contralateral to HER2 positive breast carcinoma cells inoculation site, enabling continuous secretion of trastuzumab in the brain. In the second approach, we used the same HDAd-trastuzumab viral vector, directly injected intracranially, contralateral to the HER2 positive breast carcinoma cells inoculation site. Both methods enabled therapeutic concentrations of local in-vivo production of active trastuzumab in a mouse model of brain metastatic breast cancer.RESULTSTrastuzumab secreted from the TARGT platform demonstrated in-vitro affinity and immune recruitment activity (ADCC) similar to recombinant trastuzumab (Herceptin, Genentech). When implanted in the brain of HER2 positive tumor-bearing mice, both the TARGT platform of dermal fibroblasts engineered to secrete trastuzumab and direct injection of HDAd-trastuzumab demonstrated remarkable intracranial tumor growth inhibitory effect.CONCLUSIONSThis work presents two gene therapy approaches for the administration of therapeutic antibodies to the brain. The TARGT platform of dermal fibroblasts engineered to secrete active trastuzumab, and the direct injection of HDAd-trastuzumab viral vector, both rendered continuous in-vivo secretion of active trastuzumab in the brain and demonstrated high efficacy. These two approaches present a proof of concept for promising gene therapy based administration methods for intracranial tumors as well as other brain diseases.

02 Dec 2016·Blood

Ex Vivo Gene Therapy Approach By Targt Technology for the Treatment of β-Thalassemia Intermedia

Author: Miari, Reem ; Casu, Carla ; Shapir, Nir ; Neil, Garry ; Lo Presti, Vania ; O'Hara, Emir M ; Rivella, Stefano

Abstractβ-Thalassemia intermedia or non-transfusion dependent thalassemia (NTDT) is a genetic blood disorder characterized by ineffective erythropoiesis (IE), anemia, splenomegaly and systemic iron overload mediated by down-regulation of hepcidin. Using Hbbth3/+animals affected by NTDT, we have shown that iron restriction improves anemia and reduces splenomegaly by reducing the formation of hemichromes and improving the lifespan of red blood cells (RBC; Gardenghi et al, JCI, 2010; Guo et al, JCI, 2013; Casu et all Blood 2016). These findings emphasize the strong correlation between erythropoiesis, RBC synthesis and iron metabolism. In theory, agents that can stimulate erythropoiesis (such as erythropoietin or EPO) could improve anemia by increasing the production of RBC and, under conditions of reduced iron absorption, correct the iron overload by consuming the excess of iron stored in organs. Here we used a new ex vivo technology called TARGT (Transduced Autologous Restorative Gene Therapy) for prolonged production and secretion of therapeutic agents. Primary dermal fibroblasts transduced with helper dependent adenovirus expressing mouse Epo were embedded in Matrigel and implanted in the dorsal area of 2-3 months old Hbbth3/+and wild-type (WT) C57BL/6 mice. Three groups were generated for each genotype using different amounts of genetically modified fibroblasts (10e5, 5x10e5 and 1x10e6 transduced cells), while one group received no transduced fibroblasts as control. Complete blood count and serum harvest for Epo levels measurement were performed one week after implantation and then every ten days until the end of the experiment, at six weeks. In WT mice, already one week after fibroblasts implantation, hemoglobin (Hb) levels raised 2/3 g/dL, showing erythrocytosis. At the end of the treatment animals showed significantly increased Hb levels (18.5±1.7 g/dL, 19.4±0.5 g/dL and 19.8±0.8 g/dL in the groups implanted with 10e5, 5x10e5 and 1x10e6 fibroblasts, respectively, compared to 13.5±0.8 g/dL in controls). RBC numbers and HTC follow the same trend, showing increases in the range of 27% to 39%.In Hbbth3/+mice Hb levels rose about 3 g/dl already one week after fibroblasts implantation and remained elevated until the end experiment (8.7±0.3 g/dL, 10.7±1.0 g/dL and 10.6±1.8 g/dL in the groups implanted with 10e5, 5x10e5 and 1x10e6 fibroblasts, respectively, compared to 7.7±0.7 g/dL in controls). RBC numbers and HTC follow the same trend, showing increases in the range of 7% to 27%. At the end of the treatment, serum Epo levels were markedly increased at all doses both in Hbbth3/+and WT animals (more than 50% and up to 90%) when compared with their respective controls.However, as expected, stimulation of erythropoiesis led to worsening of splenomegaly and suppression of hepcidin, likely preventing the beneficial effect of erythroid-mediated consumption of stored iron in Hbbth3/+animals. Here we postulated that, in presence of agents that increase erythropoiesis such as Epo, some level of iron restriction is required to improve the anemia, prevent exacerbation of the splenomegaly and, concurrently, decreased iron overload. As a proof of principle of the ability of this technology to improve anemia and decrease iron overload, TARGTEPO was combined with low iron diet or iron chelation. We expect that decreased iron intake will improve the quality of the RBC, while the larger number of RBC produced should utilize more stored iron, reversing the iron overload in Hbbth3/+animals. Preliminary results at three weeks from the beginning of the experiment indicated that in WT implanted-animals the combination of TARGTEPO with low iron diet significantly reduced Hb levels (-40%), HTC (-42%), RBC number (-38%) and reticulocytes (-80%) when compared to animals overexpressing Epo and receiving normal iron diet or iron chelation. This indicates that in WT animals, after 3 weeks, the stored iron is insufficient to support the increased erythropoiesis. In contrast, in Hbbth3/+animals this drop in Hb was not seen, suggesting that this effect is delayed due to the highest level of stored iron. Complete characterization of these models and their parameters is in progress. These preliminary results suggest that the TARGTplatformcould be utilized, in combination with drugs that limit iron intake, to improve anemia and decrease iron overload in NTDT. Additional experiments are in progress to test this hypothesis.DisclosuresCasu: Ionis Pharmaceuticals: Research Funding; Medgenics LLC: Research Funding; Merganser Biotech: Research Funding. Neil:Medgenics: Employment. Miari:Medgenics: Employment. Shapir:Medgenics: Employment.

100 Deals associated with Medgenics Medical (Israel) Ltd.

100 Translational Medicine associated with Medgenics Medical (Israel) Ltd.

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