ABSTRACT
BACKGROUND: MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. METHODS: INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti-host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). RESULTS: Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999). CONCLUSIONS: In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. TRIAL REGISTRATION: ClinicalTrials.gov, INSTRIDE 1 ( NCT02227862 ; date of registration, August 28, 2014); INSTRIDE 2 ( NCT02227875 ; date of registration, August 28, 2014).
Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Immunogenetic Phenomena/drug effects , Insulin Glargine/therapeutic use , Adult , Biosimilar Pharmaceuticals/pharmacology , Biosimilar Pharmaceuticals/therapeutic use , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/immunology , Female , Humans , Hypoglycemic Agents/pharmacology , Immunogenetic Phenomena/physiology , Insulin Glargine/pharmacology , Male , Middle AgedABSTRACT
AIM: Tregopil, a novel PEGylated human insulin is in clinical development for oral delivery in diabetes treatment. The aim of the study was to develop and validate a sensitive and specific ELISA method for quantitating Tregopil in diabetes subjects on basal Glargine, since most commercially available insulin kits either do not detect Tregopil or show significant reactivity to Glargine. METHODS: An electrochemiluminescent ELISA was developed and validated for Tregopil quantitation in diabetes serum. RESULTS: The method has a LLOQ of 0.25 ng/ml, shows minimum cross-reactivity to Glargine and was successfully tested using a subset of samples from Tregopil-dosed Type 1 diabetes mellitus patients. CONCLUSION: The ELISA method is sensitive and can be used to support accurate measurement of Tregopil with no cross-reactivity to Glargine and its metabolites in clinical studies.
Subject(s)
Blood Chemical Analysis/methods , Diabetes Mellitus, Type 2/blood , Enzyme-Linked Immunosorbent Assay/methods , Insulin/analogs & derivatives , Administration, Oral , Electrochemistry , Humans , Insulin/administration & dosage , Insulin/blood , Limit of Detection , Luminescent Measurements , Polyethylene Glycols/administration & dosage , Quality ControlABSTRACT
Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid catabolism. Here, we provide evidence that PPARα is constitutively expressed in nuclei of hippocampal neurons and, surprisingly, controls calcium influx and the expression of various plasticity-related genes via direct transcriptional regulation of cyclic AMP response element binding (CREB). Accordingly, Pparα-null, but not Pparß-null, mice are deficient in CREB and memory-associated proteins and have decreased spatial learning and memory. Small hairpin RNA knockdown of PPARα in the hippocampus suppressed CREB and NR2A, rendering wild-type animals markedly poor in consolidating spatial memory, whereas introduction of PPARα to the hippocampus of Pparα-null mice increased hippocampal CREB and NR2A and improved spatial learning and memory. Through detailed analyses of CREB and NR2A activity, as well as spatial learning and memory in bone marrow chimeric animals lacking PPARα in the CNS, we uncover a mechanism for transcriptional control of Creb and associated plasticity genes by PPARα.
Subject(s)
Cyclic AMP Response Element-Binding Protein/metabolism , Gene Expression Regulation , Hippocampus/metabolism , PPAR alpha/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Response Elements , Animals , Calcium/metabolism , Cyclic AMP Response Element-Binding Protein/genetics , Hippocampus/cytology , Hippocampus/physiology , Macaca mulatta , Maze Learning , Memory , Mice , Mice, Inbred C57BL , Neurons/metabolism , PPAR alpha/genetics , Protein Binding , Receptors, N-Methyl-D-Aspartate/genetics , Synapses/metabolism , Synapses/physiology , Transcription, GeneticABSTRACT
Huntington's disease (HD) is a neurodegenerative disease for which there is no cure. Therapies that are efficacious in animal models have to date shown benefit for humans. One potential powerful approach is gene therapy. The ideal method of administration of gene therapy has been hotly debated and viral vectors have provided one method of long-term and wide-spread delivery to the brain. Trophic factors to protect cells from degeneration and RNAi to reduce mutant huntingtin (mHtt) protein expression are 2 main classes of compounds that demonstrate benefit in animal models. This review will examine some commonly used adeno-associated viral (AAV) vectors and discuss some therapies that hold promise for HD.
Subject(s)
Genetic Therapy/methods , Huntington Disease/therapy , Adenoviridae/genetics , Animals , Brain-Derived Neurotrophic Factor/genetics , Ciliary Neurotrophic Factor/genetics , Genetic Vectors , Glial Cell Line-Derived Neurotrophic Factor/genetics , Humans , RNA InterferenceABSTRACT
Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no effective neuroprotective therapy. Patients are typically treated with a combination of drug therapies and/or receive deep brain stimulation to combat behavioral symptoms. The ideal candidate therapy would be the one which prevents neurodegeneration in the brain, thereby halting the progression of debilitating disease symptoms. Neurotrophic factors have been in the forefront of PD research, and clinical trials have been initiated using members of the GDNF family of ligands (GFLs). GFLs have been shown to be trophic to ventral mesencephalic cells, thereby making them good candidates for PD research. This paper examines the use of GDNF and neurturin, two members of the GFL, in both animal models of PD and clinical trials.
Subject(s)
Genetic Therapy/methods , Nerve Growth Factors/therapeutic use , Parkinson Disease/therapy , Animals , Clinical Trials as Topic , HumansABSTRACT
Members of the GDNF family of ligands, including neurturin (NTN), have been implicated as potential therapeutic agents for Huntington's disease (HD). The present study examined the ability of CERE-120 (AAV2-NTN) to provide structural and functional protection in the N171-82Q transgenic HD mouse model. AAV2-NTN therapy attenuated rotorod deficits in this mutant relative to control treated transgenics (p<0.01). AAV2-NTN treatment significantly reduced the number of transgenic mice that exhibited clasping behavior and partially restored their stride lengths (both p<0.05). Stereological counts of NeuN-ir neurons revealed a significant neuroprotection in the striatum of AAV2-NTN treated relative to control treated transgenics (p<0.001). Most fascinating, stereological counts of NeuN-labeled cells in layers V-VI of prefrontal cortex revealed that intrastriatal AAV2-NTN administration prevented the loss of frontal cortical NeuN-ir neurons seen in transgenic mice (p<0.01). These data indicate that gene delivery of NTN may be a viable strategy for the treatment of this incurable disease.
Subject(s)
Cerebral Cortex/physiopathology , Corpus Striatum/physiopathology , Genetic Therapy , Huntington Disease/therapy , Motor Activity , Neurons/physiology , Neurturin/genetics , Animals , DNA-Binding Proteins , Dependovirus/genetics , Disease Models, Animal , Gene Expression , Gene Transfer Techniques , Genetic Vectors , Huntingtin Protein , Huntington Disease/genetics , Huntington Disease/physiopathology , Mice , Mice, Transgenic , Mutation , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurturin/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Random Allocation , Rotarod Performance TestABSTRACT
Growth factors are potentially major players in therapeutic interventions for neurodegenerative disorders like Parkinson's disease (PD) because of their potential to not merely provide symptomatic relief but also be disease modifying agents. Many extensively utilized therapies such as the prodrug levodopa, while unquestionably effective, are intended for symptomatic benefit. Such therapies do little to stifle the progressive nature of these diseases thereby placing temporal restrictions on their effectiveness. Growth factors, by virtue of their distinct neuroprotective properties, have the cumulative effect of curbing disease progression and allaying existing symptoms. The purpose of this review is to discuss some of the growth factors commonly used in animal models of PD and those already used in clinical trials.
Subject(s)
Intercellular Signaling Peptides and Proteins , Parkinson Disease/metabolism , Parkinson Disease/therapy , Animals , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/therapeutic useABSTRACT
Huntington's disease (HD) is a neurological disorder caused by a genetic mutation in the IT15 gene. Progressive cell death in the striatum and cortex, and accompanying declines in cognitive, motor, and psychiatric functions, are characteristic of the disease. Animal models of HD have provided insight into disease pathology and the outcomes of therapeutic strategies. Earlier studies of HD most often used toxin-induced models to study mitochondrial impairment and excitotoxicity-induced cell death, which are both mechanisms of degeneration seen in the HD brain. These models, based on 3-nitropropionic acid and quinolinic acid, respectively, are still often used in HD studies. The discovery in 1993 of the huntingtin mutation led to the creation of newer models that incorporate a similar genetic defect. These models, which include transgenic and knock-in rodents, are more representative of the HD progression and pathology. An even more recent model that uses a viral vector to encode the gene mutation in specific areas of the brain may be useful in nonhuman primates, as it is difficult to produce genetic models in these species. This article examines the aforementioned models and describes their use in HD research, including aspects of the creation, delivery, pathology, and tested therapies for each model.
Subject(s)
Disease Models, Animal , Huntington Disease , Animals , Disease Progression , Genetic Vectors , Huntington Disease/etiology , Huntington Disease/pathology , Huntington Disease/therapy , Lentivirus/genetics , Mice , Nitro Compounds/pharmacology , Organisms, Genetically Modified , Primates , Propionates/pharmacology , Quinolinic Acid/pharmacology , RatsABSTRACT
Huntington's disease (HD) is a devastating neurodegenerative disorder that occurs in patients with a mutation in the huntingtin or IT15 gene. Patients are plagued by early cognitive signs, motor deficits, and psychiatric disturbances. Symptoms are attributed to cell death in the striatum and disruption of cortical-striatal circuitry. Mechanisms of cell death are unclear, but processes involving mitochondrial abnormalities, excitotoxicity, and abnormal protein degradation have been implicated. Many factors likely contribute to neuron death and dysfunction, and this has made it difficult to systematically address the pathology in HD. Pharmaceutical therapies are commonly used in patients to treat disease symptoms. These have limited benefit and do not address the inexorable disease progression. Several neuroprotective therapies are being evaluated in animal models of HD as well as in clinical trials. Similarly, cell replacement strategies such as fetal transplantation have been used in the clinic with minimal success, making future cell replacement strategies such as stem cell therapy uncertain. This review describes the disease pathology in HD and addresses many of the past and emerging therapeutic strategies.
Subject(s)
Huntington Disease , Cell Death , Fetal Tissue Transplantation , Humans , Huntington Disease/genetics , Huntington Disease/pathology , Huntington Disease/physiopathology , Huntington Disease/therapy , Intercellular Signaling Peptides and Proteins/therapeutic use , Neuroprotective Agents/therapeutic useABSTRACT
Huntington's disease (HD) is a devastating neurodegenerative disease characterized by the selective loss of neurons in the striatum and cerebral cortex. This study tested the hypothesis that an adenoassociated viral (AAV2) vector encoding for the trophic factor neurturin (NTN) could provide neuroprotection in the rat 3-nitropropionic acid (3NP) model of HD. Rats received AAV2-NTN (CERE-120), AAV2-eGFP or Vehicle, followed 4 weeks later by the mitochondrial toxin 3NP. 3NP induced motor impairments were observed on the rotarod test, the platform test, and a clinical rating scale in all groups. However, each of these deficits was attenuated by AAV2-NTN (CERE-120). Stereological counts revealed a significant protection of NeuN-ir striatal neurons from 3NP toxicity by AAV2-NTN. These data support the concept that AAV2-NTN might be a valuable treatment for patients with Huntington's disease.
Subject(s)
Corpus Striatum/metabolism , Genetic Therapy/methods , Huntington Disease/therapy , Nerve Degeneration/therapy , Neurons/metabolism , Neurturin/genetics , Animals , Cell Count , Cell Death/genetics , Corpus Striatum/drug effects , Corpus Striatum/physiopathology , Cytoprotection/genetics , DNA-Binding Proteins , Dependovirus/genetics , Disease Models, Animal , Gene Transfer Techniques/trends , Genetic Vectors/genetics , Huntington Disease/chemically induced , Huntington Disease/genetics , Male , Motor Activity/genetics , Nerve Degeneration/physiopathology , Nerve Degeneration/prevention & control , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/pathology , Neurotoxins , Neurturin/therapeutic use , Nitro Compounds , Nuclear Proteins/metabolism , Propionates , Rats , Rats, Inbred Lew , Recovery of Function/genetics , Treatment OutcomeABSTRACT
Huntington's disease (HD) is a fatal, genetic, neurological disorder resulting from a trinucleotide repeat expansion in the gene that encodes for the protein huntingtin. These excessive repeats confer a toxic gain of function on huntingtin, which leads to the degeneration of striatal and cortical neurons and a devastating motor, cognitive, and psychological disorder. Trophic factor administration has emerged as a compelling potential therapy for a variety of neurodegenerative disorders, including HD. We previously demonstrated that viral delivery of glial cell line-derived neurotrophic factor (GDNF) provides structural and functional neuroprotection in a rat neurotoxin model of HD. In this report we demonstrate that viral delivery of GDNF into the striatum of presymptomatic mice ameliorates behavioral deficits on the accelerating rotorod and hind limb clasping tests in transgenic HD mice. Behavioral neuroprotection was associated with anatomical preservation of the number and size of striatal neurons from cell death and cell atrophy. Additionally, GDNF-treated mice had a lower percentage of neurons containing mutant huntingtin-stained inclusion bodies, a hallmark of HD pathology. These data further support the concept that viral vector delivery of GDNF may be a viable treatment for patients suffering from HD.
Subject(s)
Gene Transfer Techniques , Glial Cell Line-Derived Neurotrophic Factors/metabolism , Huntington Disease/pathology , Huntington Disease/physiopathology , Neuroprotective Agents/metabolism , Animals , Behavior, Animal/physiology , Cell Death , Corpus Striatum/cytology , Corpus Striatum/metabolism , Dependovirus/genetics , Dependovirus/metabolism , Disease Models, Animal , Female , Genetic Therapy , Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism , Glial Cell Line-Derived Neurotrophic Factors/genetics , Glial Cell Line-Derived Neurotrophic Factors/therapeutic use , Humans , Huntingtin Protein , Huntington Disease/genetics , Huntington Disease/therapy , Inclusion Bodies/chemistry , Male , Mice , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Neurons/cytology , Neurons/metabolism , Neuroprotective Agents/therapeutic use , Nuclear Proteins/metabolism , RatsABSTRACT
Neurogenesis following neural degeneration has been demonstrated in many models of disease and injury. The present study further examines the early proliferative and migratory response of the brain to a controlled cortical impact (CCI) model of traumatic brain injury. The CCI was centered over the forelimb sensorimotor cortex, unilaterally, in the adult mouse. To examine proliferation, bromo-deoxyuridine (BrdU) was injected i.p. immediately post-injury and on post-injury days 1, 2, and 3. To assess migration, we labeled SVZ cells with inert latex microspheres immediately post-injury. By combining microsphere labeling with BrdU, we determined if migrating cells had gone through the S-phase of the cell cycle after the lesion. In addition, we used a marker of neurogenesis and migration, doublecortin, to further characterize the response of the SVZ to the injury. Lastly, we determined whether subregions of the SVZ respond differentially to injury. The current study demonstrates that 3 days following CCI cellular proliferation is seen around the cortex, in the SVZ, corpus callosum, and subcortical areas anatomically connected to, but not directly damaged by the impact. It delineates that an increase in proliferation occurs in the dorsal-most aspect of the ipsilateral SVZ following impact. Lastly, it demonstrates that proliferating cells migrate from the SVZ to cortical and subcortical structures affected by the injury and that some of these cells are migrating neuroblasts.