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Article ; Online: 5-aza-2'-deoxycytidine induces apoptosis and inhibits tumour growth in vivo of FaDu cells, a specific HPVnegative HNSCC cell line.

Miari, Reem / Azzam, Naiel / Bar-Shalom, Rinat / Fares, Fuad

PloS one

2021 Volume 16, Issue 9, Page(s) e0253756

Abstract: Head and neck cancer squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 600,000 new diagnoses annually. Traditionally, HNCC has been related to tobacco and alcohol exposure; however, over the past decade, a ... ...

Abstract	Head and neck cancer squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 600,000 new diagnoses annually. Traditionally, HNCC has been related to tobacco and alcohol exposure; however, over the past decade, a growing number of head and neck cancers are attributed to human papillomavirus (HPV) infection. 5-Aza-2'-deoxycytidine (5-AzaD) was demonstrated as an effective chemotherapeutic agent for acute myelogenous leukaemia. Preclinical data revealed that 5-aza inhibits growth and increases cell death of HPV(+) cancer cells. These effects are associated with reduced expression of HPV genes, stabilization of TP53, and activation of TP53-dependent apoptosis. The aim of the present study is to test the effect of 5-AzaD on growth of human squamous cell carcinoma (FaDu), a HPV(-) and p53 mutated cells, in vitro and in vivo. The effect of 5-AzaD on cell viability, cell cycle progression and induction of apoptosis was tested in vitro. The effect of 5-AzaD on tumour growth in vivo was tested using xenograft mice inoculated with FaDu cells. The results indicated that 5-AzaD reduced cell viability and induced apoptosis in FaDu cells in vitro. In vivo studies revealed that 5-AzaD suppresses the growth of tumours in xenograft mice inoculated with FaDu cells through inhibition of proliferation and induction of apoptosis. These findings may emphasis that 5-AzaD is effective in treatment of HPV(-) HNSCC tumours through TP53 independent pathway. Future studies are needed in order to clarify the molecular mechanism of action of 5-AzaD in HPV(-) cancer cells.
MeSH term(s)	Animals ; Antimetabolites, Antineoplastic/administration & dosage ; Antimetabolites, Antineoplastic/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Decitabine/administration & dosage ; Decitabine/pharmacology ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic/drug effects ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/genetics ; Humans ; Male ; Mice ; Mutation ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; Squamous Cell Carcinoma of Head and Neck/genetics ; Tumor Suppressor Protein p53/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	Antimetabolites, Antineoplastic ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Decitabine (776B62CQ27)
Language	English
Publishing date	2021-09-17
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0253756
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Article ; Online: Inhibiting mutant KRAS G12D gene expression using novel peptide nucleic acid-based antisense: A potential new drug candidate for pancreatic cancer.

Shai, Ayelet / Galouk, Evleen / Miari, Reem / Tareef, Hala / Sammar, Marei / Zeidan, Mouhammad / Rayan, Anwar / Falah, Mizied

Oncology letters

2022 Volume 23, Issue 4, Page(s) 130

Abstract: KRAS mutations, which are the main cause of the pathogenesis of lethal pancreatic adenocarcinomas, impair the functioning of the GTPase subunit, thus rendering it constitutively active and signaling intracellular pathways that end with cell ... ...

Abstract	KRAS mutations, which are the main cause of the pathogenesis of lethal pancreatic adenocarcinomas, impair the functioning of the GTPase subunit, thus rendering it constitutively active and signaling intracellular pathways that end with cell transformation. In the present study, the AsPC-1 cell line, which has a G12D-mutated KRAS gene sequence, was utilized as a cellular model to test peptide nucleic acid-based antisense technology. The use of peptide nucleic acids (PNAs) that are built to exhibit improved hybridization specificity and have an affinity for complementary RNA and DNA sequences, as well as a simple chemical structure and high biological stability that affords resistance to nucleases and proteases, enabled targeting of the KRAS-mutated gene to inhibit its expression at the translation level. Because PNA-based antisense molecules should be capable of binding to KRAS mRNA sequences, PNAs were utilized to target the mRNA of the mutated KRAS gene, a strategy that could lead to the development of a novel drug for pancreatic cancer. Moreover, it was demonstrated that introducing new PNA to cells inhibited the growth of cancer cells and induced apoptotic death and, notably, that it can inhibit G12D-mutated KRAS gene expression, as demonstrated by RT-PCR and western blotting. Altogether, these data strongly suggest that the use of PNA-based antisense agents is an attractive therapeutic approach to treating KRAS-driven cancers and may lead to the development of novel drugs that target the expression of other mutated genes.
Language	English
Publishing date	2022-02-21
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2573196-8
ISSN	1792-1082 ; 1792-1074
ISSN (online)	1792-1082
ISSN	1792-1074
DOI	10.3892/ol.2022.13250
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Article ; Online: Forty-One Plant Extracts Screened for Dual Antidiabetic and Antioxidant Functions: Evaluating the Types of Correlation between -Amylase Inhibition and Free Radical Scavenging.

Bashkin, Amir / Ghanim, Manar / Abu-Farich, Basheer / Rayan, Mahmoud / Miari, Reem / Srouji, Samer / Rayan, Anwar / Falah, Mizied

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 2

Abstract: Dysregulation of glucose homeostasis followed by chronic hyperglycemia is a hallmark of diabetes mellitus (DM), a disease spreading as a worldwide pandemic for which there is no satisfactory dietary treatment or cure. The development of glucose- ... ...

Abstract	Dysregulation of glucose homeostasis followed by chronic hyperglycemia is a hallmark of diabetes mellitus (DM), a disease spreading as a worldwide pandemic for which there is no satisfactory dietary treatment or cure. The development of glucose-controlling drugs that can prevent complications of DM, such as hyperglycemia and oxidative stress, which contribute to the impairment of the key physiological processes in the body, is of grave importance. In pursuit of this goal, this study screened 41 plant extracts for their antidiabetic and antioxidant activities by employing assays to test for α-amylase inhibition and free radical scavenging activity (FRSA) and by measuring glucose uptake in L6-GLUT4myc cells. While extracts of Rhus coriaria, Punica granatum, Olea europaea, Pelargonium spp., Stevia rebaudiana, and Petroselinum crispum demonstrated significant α-amylase inhibition, the extracts of Rhus coriaria and Pelargonium spp. also demonstrated increased FRSA, and the extract of Rhus coriaria stimulated glucose uptake. These natural extracts, which are believed to have fewer side effects because they are prepared from edible plants, interfere with the process in the small intestine that breaks down dietary carbohydrates into monosaccharide and disaccharide derivatives, and thereby suppress increases in diet-induced blood glucose; hence, they may have clinical value for type 2 diabetes management. The Pelargonium spp. and Rhus coriaria extracts demonstrated the highest antidiabetic and antioxidant activities. Both plants may offer valuable medical benefits, especially because they can be taken as dietary supplements by patients with diabetes and can serve as sources of new, natural-based antidiabetic drug candidates. The enhancement of cellular glucose uptake stimulated by Rhus coriaria extract could lead to the development of clinical applications that regulate blood glucose levels from within the circulatory system. Isolating bioactive substances from these plant extracts and testing them in diabetic mice will significantly advance the development of natural drugs that have both antidiabetic and free radical-scavenging properties, likely with lesser side effects.
MeSH term(s)	Animals ; Antioxidants/chemistry ; Antioxidants/isolation & purification ; Antioxidants/pharmacology ; Biphenyl Compounds/antagonists & inhibitors ; Cell Survival/drug effects ; Cells, Cultured ; Diabetes Mellitus, Experimental/drug therapy ; Diabetes Mellitus, Type 2/drug therapy ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/isolation & purification ; Enzyme Inhibitors/pharmacology ; Humans ; Hypoglycemic Agents/chemistry ; Hypoglycemic Agents/isolation & purification ; Hypoglycemic Agents/pharmacology ; Mice ; Pelargonium/chemistry ; Picrates/antagonists & inhibitors ; Plant Extracts/chemistry ; Plant Extracts/isolation & purification ; Plant Extracts/pharmacology ; Rhus/chemistry ; alpha-Amylases/antagonists & inhibitors ; alpha-Amylases/metabolism
Chemical Substances	Antioxidants ; Biphenyl Compounds ; Enzyme Inhibitors ; Hypoglycemic Agents ; Picrates ; Plant Extracts ; 1,1-diphenyl-2-picrylhydrazyl (DFD3H4VGDH) ; alpha-Amylases (EC 3.2.1.1)
Language	English
Publishing date	2021-01-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26020317
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Article ; Online: Preclinical and Preliminary Clinical Evaluation of Genetically Transduced Dermal Tissue Implants for the Sustained Secretion of Erythropoietin and Interferon α.

Shapir, Nir / Miari, Reem / Blum, Shany / Schwartz, Doron / Chernin, Gil / Neil, Garry A / Afik, Daniel / Panet, Amos

Human gene therapy. Clinical development

2015 Volume 26, Issue 4, Page(s) 216–227

Abstract: Protein drugs are currently delivered by bolus injection and although treatment frequently is successful, these methods also have major drawbacks, which call for the development of alternative technologies allowing prolonged delivery of these drugs. We ... ...

Abstract	Protein drugs are currently delivered by bolus injection and although treatment frequently is successful, these methods also have major drawbacks, which call for the development of alternative technologies allowing prolonged delivery of these drugs. We developed a new ex vivo gene therapy platform called Transduced Autologous Restorative Gene Therapy (TARGT) for sustained long term production and secretion of autologous therapeutic proteins. A biopsy of dermal tissue taken from the patient is transduced ex vivo with a viral vector encoding the required gene under a constitutive promoter. Following measurement of protein secretion ex vivo, the transduced dermal tissue is implanted back into the patient, where it secretes the therapeutic protein into the circulation for several months or longer. A major hurdle to this approach is potential immunogenicity of the transduced tissue following implantation. In this paper we describe the preclinical and early clinical development of this technology, which allowed for overcoming these hurdles. To that end, we have used the helper dependent (HD) adenoviral vector with newly designed expression cassette containing genetic elements to optimize transgene expression. Moreover, we have developed procedures for TARGT tissue implantation, with measures to improve engraftment and reduce inflammation and rejection. Implantation of human TARGT to severe combined immune deficient (SCID) mice indicated long-term production of active proteins in the blood. Preliminary results of a clinical trial from two anemic end-stage renal disease patients, implanted with TARGTs expressing the human erythropoietin (EPO) gene, demonstrated prolonged secretion with physiologic blood level of the hormone and hemoglobin maintenance in the desired range, for a period of at least 5 months without exogenous EPO administration. We believe that the TARGT technology has the potential to become a platform for the sustained delivery of therapeutic proteins in various clinical indications.
MeSH term(s)	Adenoviridae/genetics ; Adult ; Aged ; Animals ; Erythropoietin/blood ; Erythropoietin/genetics ; Erythropoietin/metabolism ; Genetic Therapy/adverse effects ; Genetic Therapy/methods ; Humans ; Interferon-alpha/blood ; Interferon-alpha/genetics ; Interferon-alpha/metabolism ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Renal Insufficiency/therapy ; Skin Transplantation/adverse effects ; Skin Transplantation/methods
Chemical Substances	Interferon-alpha ; Erythropoietin (11096-26-7)
Language	English
Publishing date	2015-12
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	2768506-8
ISSN	2324-8645 ; 2324-8637
ISSN (online)	2324-8645
ISSN	2324-8637
DOI	10.1089/humc.2015.125
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Zs.A 7036: Show issues

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Article ; Online: Correcting β-thalassemia by combined therapies that restrict iron and modulate erythropoietin activity.

Blood

2020 Volume 136, Issue 17, Page(s) 1968–1979

Abstract: β-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 ... ...

Abstract	β-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.
MeSH term(s)	Animals ; Cells, Cultured ; Erythropoiesis/drug effects ; Erythropoiesis/genetics ; Erythropoietin/administration & dosage ; Erythropoietin/genetics ; Gene Expression Regulation/drug effects ; Genetic Therapy/methods ; Iron/metabolism ; Iron Overload/genetics ; Iron Overload/prevention & control ; Male ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Oligonucleotides, Antisense/administration & dosage ; Oligonucleotides, Antisense/pharmacology ; Receptors, Transferrin/genetics ; Serine Endopeptidases/genetics ; Serine Endopeptidases/metabolism ; beta-Thalassemia/metabolism ; beta-Thalassemia/therapy
Chemical Substances	Epo protein, mouse ; Membrane Proteins ; Oligonucleotides, Antisense ; Receptors, Transferrin ; TFR2 protein, mouse ; Erythropoietin (11096-26-7) ; Iron (E1UOL152H7) ; Serine Endopeptidases (EC 3.4.21.-) ; matriptase 2 (EC 3.4.21.-)
Language	English
Publishing date	2020-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2019004719
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Biopump: Autologous skin-derived micro-organ genetically engineered to provide sustained continuous secretion of therapeutic proteins.

Mitrani, Eduardo / Pearlman, Andrew / Stern, Baruch / Miari, Reem / Goltsman, Haim / Kunicher, Nikolai / Panet, Amos

Dermatologic therapy

2011 Volume 24, Issue 5, Page(s) 489–497

Abstract: A novel approach for sustained production of therapeutic proteins is described, using genetic modification of intact autologous micro-organ tissue explants from the subject's own skin. The skin-derived micro-organ can be maintained viable ex vivo for ... ...

Abstract	A novel approach for sustained production of therapeutic proteins is described, using genetic modification of intact autologous micro-organ tissue explants from the subject's own skin. The skin-derived micro-organ can be maintained viable ex vivo for extended periods and is transduced with a transgene encoding a desired therapeutic protein, resulting in protein-secreting micro-organ (biopump (BP)). The daily protein production from each BP is quantified, enabling drug dosing by subcutaneous implantation of the requisite number of BPs into the patient to provide continuous production to the circulation of a known amount of the therapeutic protein. Each implanted BP remains localized and is accessible, to enable removal or ablation if needed. Examples from preclinical and clinical studies are presented, including use of associated virus vector 1 and helper-dependent adenoviral vectors producing BPs to provide long-term sustained secretion of recombinant interferon-α and erythropoietin.
MeSH term(s)	Adenoviridae ; Animals ; Erythropoietin/biosynthesis ; Erythropoietin/genetics ; Genetic Therapy/methods ; Genetic Vectors ; Humans ; Interferon-alpha/biosynthesis ; Interferon-alpha/genetics ; Lentivirus ; Skin/metabolism ; Skin/secretion ; Skin Transplantation ; Tissue Culture Techniques ; Transduction, Genetic
Chemical Substances	Interferon-alpha ; Erythropoietin (11096-26-7)
Language	English
Publishing date	2011-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1354801-3
ISSN	1529-8019 ; 1396-0296
ISSN (online)	1529-8019
ISSN	1396-0296
DOI	10.1111/j.1529-8019.2012.01457.x
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Zs.A 5181: Show issues

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Article ; Online: TARGT Gene Therapy Platform for Correction of Anemia in End-Stage Renal Disease.

Blum, Shany / Shapir, Nir / Miari, Reem / Lerner, Benny / Koren, Belly / Doenyas-Barak, Keren / Efrati, Shai / Pergola, Pablo E / Schwartz, Doron / Chernin, Gil / Yagil, Yoram / Guzy, Serge / Nyska, Abraham / Neil, Garry A

The New England journal of medicine

2017 Volume 376, Issue 2, Page(s) 189–191

MeSH term(s)	Anemia/etiology ; Anemia/therapy ; Animals ; Drug Implants ; Erythropoietin/blood ; Erythropoietin/secretion ; Genetic Therapy/methods ; Hemoglobins/analysis ; Humans ; Kidney Failure, Chronic/complications ; Kidney Failure, Chronic/therapy ; Mice ; Renal Dialysis
Chemical Substances	Drug Implants ; Hemoglobins ; Erythropoietin (11096-26-7)
Language	English
Publishing date	2017--12
Publishing country	United States
Document type	Letter
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMc1606202
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Article ; Online: Sustained secretion of anti-tumor necrosis factor α monoclonal antibody from ex vivo genetically engineered dermal tissue demonstrates therapeutic activity in mouse model of rheumatoid arthritis.

Zafir-Lavie, Inbal / Miari, Reem / Sherbo, Shay / Krispel, Simi / Tal, Osnat / Liran, Atar / Shatil, Tamar / Badinter, Felix / Goltsman, Haim / Shapir, Nir / Benhar, Itai / Neil, Garry A / Panet, Amos

The journal of gene medicine

2017 Volume 19, Issue 8

Abstract: Background: Rheumatoid arthritis (RA) is a symmetric inflammatory polyarthritis associated with high concentrations of pro-inflammatory, cytokines including tumor necrosis factor (TNF)-α. Adalimumab is a monoclonal antibody (mAb) that binds TNF-α, and ... ...

Abstract	Background: Rheumatoid arthritis (RA) is a symmetric inflammatory polyarthritis associated with high concentrations of pro-inflammatory, cytokines including tumor necrosis factor (TNF)-α. Adalimumab is a monoclonal antibody (mAb) that binds TNF-α, and is widely used to treat RA. Despite its proven clinical efficacy, adalimumab and other therapeutic mAbs have disadvantages, including the requirement for repeated bolus injections and the appearance of treatment limiting anti-drug antibodies. To address these issues, we have developed an innovative ex vivo gene therapy approach, termed transduced autologous restorative gene therapy (TARGT), to produce and secrete adalimumab for the treatment of RA. Methods: Helper-dependent (HD) adenovirus vector containing adalimumab light and heavy chain coding sequences was used to transduce microdermal tissues and cells of human and mouse origin ex vivo, rendering sustained secretion of active adalimumab. The genetically engineered tissues were subsequently implanted in a mouse model of RA. Results: Transduced human microdermal tissues implanted in SCID mice demonstrated 49 days of secretion of active adalimumab in the blood, at levels of tens of microgram per milliliter. In addition, transduced autologous dermal cells were implanted in the RA mouse model and demonstrated statistically significant amelioration in RA symptoms compared to naïve cell implantation and were similar to recombinant adalimumab bolus injections. Conclusions: The results of the present study report microdermal tissues engineered to secrete active adalimumab as a proof of concept for sustained secretion of antibody from the novel ex vivo gene therapy TARGT platform. This technology may now be applied to a range of antibodies for the therapy of other diseases.
Language	English
Publishing date	2017-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1458024-x
ISSN	1521-2254 ; 1099-498X
ISSN (online)	1521-2254
ISSN	1099-498X
DOI	10.1002/jgm.2965
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Zs.A 5423: Show issues

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Article ; Online: Successful intracranial delivery of trastuzumab by gene-therapy for treatment of HER2-positive breast cancer brain metastases.

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

Journal of controlled release : official journal of the Controlled Release Society

2018 Volume 291, Page(s) 80–89

Abstract: Background: Trastuzumab 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 ...

Abstract	Background: Trastuzumab 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. Methods: We 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. Results: Trastuzumab 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. Conclusions: This 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.
MeSH term(s)	Adenoviridae/genetics ; Animals ; Antineoplastic Agents, Immunological/administration & dosage ; Antineoplastic Agents, Immunological/metabolism ; Antineoplastic Agents, Immunological/therapeutic use ; Brain Neoplasms/pathology ; Brain Neoplasms/secondary ; Brain Neoplasms/therapy ; Breast Neoplasms/pathology ; Breast Neoplasms/therapy ; Cells, Cultured ; Drug Delivery Systems/methods ; Female ; Fibroblasts/metabolism ; Fibroblasts/transplantation ; Gene Transfer Techniques ; Genetic Therapy/methods ; Genetic Vectors/genetics ; Genetic Vectors/therapeutic use ; Humans ; Immunotherapy/methods ; Mice ; Mice, Inbred BALB C ; Transduction, Genetic ; Trastuzumab/administration & dosage ; Trastuzumab/genetics ; Trastuzumab/therapeutic use
Chemical Substances	Antineoplastic Agents, Immunological ; Trastuzumab (P188ANX8CK)
Language	English
Publishing date	2018-10-17
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2018.10.017
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Zs.A 2055: Show issues

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Article ; Online: Modulation of excessive neuronal activity by fibroblasts: potential use in treatment of Parkinson's disease.

Finberg, John P M / Gluzman, Zoya / Reshef, Michal / Loboda, Yelena / Mohsen, Usama / Bressler-Stramer, Tal / Miari, Reem / Gepstein, Lior / Marom, Shimon / Feld, Yair

Restorative neurology and neuroscience

2010 Volume 28, Issue 6, Page(s) 803–815

Abstract: Purpose: A number of neurological disorders are marked by increased or aberrant frequency of neuronal discharge in specific parts of the brain. Administration of drugs such as antiepileptic compounds results in the depression of neuronal activity in the ...

Abstract	Purpose: A number of neurological disorders are marked by increased or aberrant frequency of neuronal discharge in specific parts of the brain. Administration of drugs such as antiepileptic compounds results in the depression of neuronal activity in the whole brain, with the potential for serious side-effects. In the search for additional therapies to reduce the unphysiological electrical activity of over-active brain foci, we have examined the effect of fibroblasts transplanted to areas responsible for motor dysfunction in hemi-parkinsonian rats, since bursting synchronous discharges in internal segment of globus pallidus (GPi) are thought to be partially responsible for the movement disorders of PD. Fibroblasts express gap junctions and ion channels, and so, when transplanted to brain tissue, can potentially modulate excessive electrical activity. Methods: Neonatal cortical neurons were cultured on multi-electrode arrays, and their electrical activity was evaluated before and after fibroblast seeding. Unilateral 6-hydroxydopamine (6-OHDA) lesion was carried out in Fischer rats. Lesioned or control rats were transplanted with either syngeneic dermal fibroblasts, microfine glass beads, ibotenic acid, or physiological saline, in the entopeduncular nucleus (EP). Apomorphine-induced rotational behavior and L-dopa-induced dyskinetic movements were evaluated before transplantation (baseline) and 2, 4, 8, 12, and 24 weeks following transplantation. Following behavioral experiments, rats were perfused with 4% formaldehyde in PBS for immunohistochemical study of the brain. Results: We demonstrate in vitro that the introduction of fibroblasts into a network of neurons does not interfere with overall functional measures of activity, while moderately altering the characteristics of synchronous neuronal discharge. In rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal dopaminergic pathway, apomorphine-induced rotations were reduced by more than 60% following ipsilateral transplantation of fibroblasts to the EP. L-Dopa-induced dyskinesia was also significantly reduced. Transplantation of inert microspheres, or chemical lesion of the same area with ibotenic acid, did not produce beneficial effects on parkinsonian symptomatology. Conclusion: Fibroblast transplantation could be an alternative treatment strategy for the parkinsonian patient.
MeSH term(s)	Animals ; Dyskinesia, Drug-Induced/physiopathology ; Dyskinesia, Drug-Induced/therapy ; Fibroblasts/transplantation ; Motor Activity/physiology ; Neurons/physiology ; Oxidopamine ; Parkinson Disease, Secondary/chemically induced ; Parkinson Disease, Secondary/physiopathology ; Parkinson Disease, Secondary/therapy ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Treatment Outcome
Chemical Substances	Oxidopamine (8HW4YBZ748)
Language	English
Publishing date	2010
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1017098-4
ISSN	1878-3627 ; 0922-6028
ISSN (online)	1878-3627
ISSN	0922-6028
DOI	10.3233/RNN-2010-0551
Database	MEDical Literature Analysis and Retrieval System OnLINE

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