Search PubMed⌕ Search

Biomedical subjects

Howard J Federoff

Publications and source records attributed to Howard J Federoff.

52 records · Page 3Linked to original sources
PubMed2003

Convergent pathobiologic model of Parkinson's disease.

The etiology of Parkinson's disease (PD) has yet to be delineated. Human genetic studies as well as neurotoxicant and transgenic animal models of PD suggest that multiple events trigger the initiation of this progressive age-related neurodegenerative disorder. In addition, we propose that despite disparate disease triggers a convergent pathobiologic pathway exists leading to cell death. The common pathway model posits that both familial and sporadic forms of Parkinson's disease obligately share a common pathophysiological substrate. Herein we discuss the evidence for a common pathway model of Parkinson's disease through a review of synuclein transgenic models and outline an approach for the identification of shared therapeutic targets. We end with a discussion of a potential alternative therapy for Parkinson's disease.

Animals↗
PubMed2002

Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue chemokine and CD40L results in augmented antitumor activity.

Development of effective antitumor immune responses depends on timely interactions of effector cells. A bimodal approach that involves coexpression of chemokines and costimulatory molecules within the tumor bed may elaborate a more optimal antitumor response. One candidate includes secondary lymphoid tissue chemokine (SLC), which promotes the colocalization of naïve, nonpolarized memory T cells and dendritic cells (DCs) within lymph nodes and Peyer's patches. CD40L-mediated DC activation could induce maturation, enhance antigen presentation, and facilitate priming of the recruited naïve T cells. To this end, the antitumor activity of SLC and CD40L expressed singly or in combination using the herpes simplex virus (HSV)-derived amplicon was examined in two murine models: A20, a B-cell lymphoma, and CT-26, an adenocarcinoma. Administration of amplicons encoding SLC (HSV-SLC) into s.c. tumors established previously resulted in heavy infiltration of CD4+ and CD8+ T cells, and DCs, and the generation of cytolytic T-cell activity. Combined transduction of either tumor with HSV-SLC and HSV-CD40L resulted in a more enhanced antitumor activity that was CD8+ T cell-dependent than observed with either vector alone. mRNA expression of the Th1 markers IFN-gamma, perforin, and interleukin 12 was detectable only in transduced regressing tumors. In addition to identifying a potent antitumor immune strategy, we show that amplicon-mediated SLC and CD40L delivery may mimic lymph node conditions necessary for priming naïve T cells within the tumor bed, and demonstrate the importance of DC activation status on antigen presentation and cytokine expression for priming of newly recruited T cells.

Adenocarcinoma↗
PubMed2002

Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.

Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N'-nitro-N-nitrosoguanidine, H2O2, and N-methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

Active Transport, Cell Nucleus↗
PubMed2002

Functional correction of established central nervous system deficits in an animal model of lysosomal storage disease with feline immunodeficiency virus-based vectors.

Gene transfer vectors based on lentiviruses can transduce terminally differentiated cells in the brain; however, their ability to reverse established behavioral deficits in animal models of neurodegeneration has not previously been tested. When recombinant feline immunodeficiency virus (FIV)-based vectors expressing beta-glucuronidase were unilaterally injected into the striatum of adult beta-glucuronidase deficient [mucopolysaccharidosis type VII (MPS VII)] mice, an animal model of lysosomal storage disease, there was bihemispheric correction of the characteristic cellular pathology. Moreover, after the injection of FIV-based vectors expressing beta-glucuronidase into brains of beta-glucuronidase-deficient mice with established impairments in spatial learning and memory, there was dramatic recovery of behavioral function. Cognitive improvement resulting from expression of beta-glucuronidase was associated with alteration in expression of genes associated with neuronal plasticity. These data suggest that enzyme replacement to the MPS VII central nervous system goes beyond restoration of beta-glucuronidase activity in the lysosome, and imparts improvements in plasticity and spatial learning.

Animals↗
PubMed2002

Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice.

Human alpha-synuclein (halpha-SYN) is implicated in the Parkinson's disease phenotype (PDP) based on a variety of studies in man, animal models, and in vitro studies. The normal function of halpha-SYN and the mechanism by which it contributes to the PDP remains unclear. We created transgenic mice expressing either wild-type (hwalpha-SYN) or a doubly mutated (hm2alpha-SYN) form of halpha-SYN under control of the 9-kb rat tyrosine hydroxylase promoter. These mice expressed halpha-SYN in cell bodies, axons, and terminals of the nigrostriatal system. The expression of halpha-SYN in nigrostriatal terminals produced effects in both constructs resulting in increased density of the dopamine transporter and enhanced toxicity to the neurotoxin MPTP. Expression of hm2alpha-SYN reduced locomotor responses to repeated doses of amphetamine and blocked the development of sensitization. Adult hwalpha-SYN-5 transgenic mice had unremarkable dopaminergic axons and terminals, normal age-related measures on two motor coordination screens, and normal age-related measures of dopamine (DA) and its metabolites. Adult hm2alpha-SYN-39 transgenic mice had abnormal axons and terminals, age-related impairments in motor coordination, and age-related reductions in DA and its metabolites. Expression of hm2alpha-SYN adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopaminergic markers.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Glucocorticoid-regulated VEGF expression in ischemic skeletal muscle.

Vascular endothelial growth factor (VEGF) is a potent neovascular inducer. Gene therapeutic delivery of a plasmid DNA encoding VEGF has been shown to impart collateral vessel development in animal models of hindlimb ischemia. Constitutive, long-lived expression of VEGF through gene transfer, however, may result in hypervascularization and/or leaky blood vessels. To that end, the introduction of regulated VEGF gene transfer technology may provide a safer and more controlled therapy for ischemic tissues. We developed a glucocorticoid-regulated plasmid vector (pNGVL-hAP/GRE(5)-vegf-pA) for modulating VEGF gene expression. This plasmid possessed five tandem repeats of the glucocorticoid-responsive element and adenovirus major-late promoter driving the expression of the VEGF(165) cDNA. Intramuscular delivery of this plasmid to mice, and subsequent treatment with the synthetic glucocorticoid dexamethasone (DEX), led to greatly enhanced VEGF expression. Similar delivery to the gracillis muscle of New Zealand white rabbits that had undergone ligation of their femoral artery to induce ischemia exhibited increased VEGF expression and collateral vessel development only in the presence of DEX. Additionally, reintroduction of DEX at a time point during which initial VEGF transgene levels had subsided resulted in a vigorous reinduction of VEGF transgene expression. This new iteration of VEGF gene delivery provides for fine-tuned angiogenic factor-based therapy for tissues requiring neovascularization.

Animals↗
PubMed2002

Reporter gene transfer induces apoptosis in primary cortical neurons.

Modern cell biologists typically use reporter genes either alone or co-expressed with a protein of interest to facilitate the localization or quantification of protein expression. Our work demonstrates that reporter genes should be used cautiously, as several common reporter gene products are toxic to primary cortical neuronal cultures. We used the herpes simplex virus-based viral amplicon vector to transduce cortical neurons with three different reporter genes and assessed whether any reporter gene products were toxic over time, by monitoring neurite disintegration and apoptosis. Toxicity varied as a function of the reporter gene, the gene product localization, and the level of reporter gene expression. Transduction of enhanced green fluorescent protein or nuclear-localized beta-galactosidase was more toxic than non-nuclear localized beta-galactosidase. This work underscores the need for careful design of gene expression constructs. Moreover, in studies where cell injury or toxicity is being evaluated, their use should be carefully considered.

Animals↗
PubMed2002

Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea.

Ototoxicity is a major dose-limiting side effect of cisplatin chemotherapy for cancer patients. We previously demonstrated in vitro that herpes simplex type 1 (HSV-1) amplicon-mediated delivery of a neurotrophin-3 (NT-3)/myc chimera protects spiral ganglion neurons (SGNs) in murine cochlear cultures from cisplatin-induced ototoxicity. To extend these findings, a newly constructed amplicon vector (HSVnt-3myc/SV40lac) that expresses the NT-3myc chimera and the Escherichia coli beta-galactosidase (lacZ) reporter gene under separate transcriptional control was initially tested in vitro and then was delivered to the cochlea of aged mice that were subsequently treated with cisplatin. Successful transduction with the new amplicon was observed in vitro as determined by its capacity to infect SGNs and to express NT-3myc mRNA and protein. To determine whether amplicon-directed NT-3myc overexpression could abrogate the ototoxicity in vivo, two groups of aged mice (CBA) were inoculated with HSVnt-3myc/SV40lac or control vector, HSVSV40lac, preceding administration of cisplatin. Cochleas inoculated with HSVnt-3myc/SV40lac harbored significantly greater numbers of surviving SGNs and showed lower incidence of cisplatin-induced apoptosis or necrosis than those injected with the control virus. These data demonstrate that HSV amplicon-mediated NT-3 delivery can attenuate the ototoxic actions of cisplatin in the peripheral auditory system of the aged mouse. The potency of NT-3 in SGN neuroprotection suggests that in vivo neurotrophin-based gene therapy is a promising preventative treatment for chemical-induced hearing disorders, and potentially for hearing degeneration due to normal aging.

Animals↗
PubMed2002

HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a B lymphocyte malignancy that remains a largely incurable disease. CLL B cells possess the ability to process and present tumor antigens but lack expression of costimulatory molecules, rendering them inefficient effectors of T-cell activation. We previously demonstrated that helper virus-free preparations of herpes simplex virus (HSV) amplicon vectors encoding CD40L efficiently transduce CLL B cells and render them capable of eliciting specific anti-tumor T-cell responses. LIGHT (TNFSF14), a member of the tumor necrosis factor (TNF) superfamily, efficiently activates both T cells and antigen-presenting cells (APCs). We employed an HSV amplicon vector expressing human LIGHT (hf-HSV-LIGHT) to transduce CLL B cells and compared the immunomodulatory function and T-cell activation induced by hf-HSV-LIGHT transduction to that observed with a CD40L-expressing HSV amplicon (hf-HSV-CD40L). hf-HSV-LIGHT transduction induced expression of endogenous B7.1, B7.2, and ICAM.1 on CLL cells, albeit to a lesser degree than that observed in response to transduction with hf-HSV-CD40L. hf-HSV-LIGHT enhanced the antigen-presenting capacity of CLL B cells, as measured by induction of T-cell proliferation in an allogeneic mixed lymphocyte tumor reaction. Finally, hf-HSV-LIGHT-transduced CLL B cells successfully stimulated the outgrowth of autologous cytotoxic T-lymphocytes in vitro. In aggregate, these data suggest that hf-HSV-LIGHT transduction may be useful for induction of immune responses to CLL and other B-cell lymphoid malignancies.

Antigen Presentation↗
PubMed2002

Efficacy of multiagent herpes simplex virus amplicon-mediated immunotherapy as adjuvant treatment for experimental hepatic cancer.

OBJECTIVE: To evaluate the use of herpes simplex viral (HSV) amplicon vectors for production of tumor vaccines and to determine if such vaccines expressing combinations of immunostimulatory agents may be effective in the treatment of experimental liver cancer. METHODS: A hepatic metastatic tumor model using CT-26 colorectal cancer in syngeneic Balb/C mice was utilized. Tumor vaccines were produced by brief (20 minutes) exposure of irradiated tumor cells to herpes amplicon vectors carrying the transgene for RANTES, B7.1, or GM-CSF. The antitumor efficacy of vaccination using tumor cells secreting GM-CSF (single agent) or a combination of RANTES/B7.1/GM-CSF (multiagent) was tested. The effect of 60% hepatectomy or T-cell depletion was also tested in this model. RESULTS: In vitro assays confirmed high-level cytokine or costimulatory molecule production by cells transduced with amplicons. Antitumor efficacy was observed with single-agent or multiagent treatment. Without hepatectomy, immunization with single-agent or multiagent vaccine therapy appears equivalent. When administered in the setting of hepatectomy, multiagent regimens produced a higher cure rate than single-agent therapy (50% vs. 12.5%, =.03). Animals treated with GM-CSF alone had an average nodule count of 40 +/- 19 ( <.006 vs. Hep control 232 +/- 30), while animals treated with multiagent therapy had an average nodule count of 11 +/- 7 ( <.0004 vs. control). CD4 and CD8 lymphocyte blockade abrogated observed efficacy, confirming a lymphocyte-mediated response. CONCLUSIONS: Tumor vaccines produced using HSV amplicon-mediated gene transfer may be useful in the treatment of liver malignancies. In the setting of hepatectomy, multiagent vaccine therapy offers an advantage over single-agent therapy. These data encourage consideration of such HSV-based neoadjuvant immunotherapy for treatment of liver malignancies.

Animals↗
PubMed2002

Expression of human immunodeficiency virus type 1 gp120 from herpes simplex virus type 1-derived amplicons results in potent, specific, and durable cellular and humoral immune responses.

Herpes simplex virus type 1 (HSV-1) infects a wide range of cells, including dendritic cells. Consequently, HSV-1 vectors may be capable of eliciting strong immune responses to vectored antigens. To test this hypothesis, an HSV-1 amplicon plasmid encoding human immunodeficiency virus type 1 gp120 was constructed, and murine immune responses to helper virus-free amplicon preparations derived from this construct were evaluated. Initial studies revealed that a single intramuscular (i.m.) injection of 10(6) infectious units (i.u.) of HSV:gp120 amplicon particles (HSV:gp120) elicited Env-specific cellular and humoral immune responses. A potent, CD8(+)-T-cell-mediated response to an H-2D(d)-restricted peptide from gp120 (RGPGRAFVTI) was measured by a gamma interferon ELISPOT and was confirmed by standard cytotoxic-T-lymphocyte assays. Immunoglobulin G enzyme-linked immunosorbent assay analysis showed the induction of a strong, Env-specific antibody response. An i.m. or an intradermal administration of HSV:gp120 at the tail base elicited a more potent cellular immune response than did an intraperitoneal (i.p.) inoculation, although an i.p. introduction generated a stronger humoral response. The immune response to HSV:gp120 was durable, with robust cellular and humoral responses persisting at 171 days after a single 10(6)-i.u. inoculation. The immune response to HSV:gp120 was also found to be dose dependent: as few as 10(4) i.u. elicited a strong T-cell response. Finally, HSV:gp120 elicited significant Env-specific cellular immune responses even in animals that had been previously infected with wild-type HSV-1. Taken together, these data strongly support the use of helper-free HSV-1 amplicon particles as vaccine delivery vectors.

Animals↗
PubMed2002

Brn3b/Brn3c double knockout mice reveal an unsuspected role for Brn3c in retinal ganglion cell axon outgrowth.

In mice, Brn3 POU domain transcription factors play essential roles in the differentiation and survival of projection neurons within the retina, inner ear, dorsal root and trigeminal ganglia. During retinal ganglion cell differentiation, Brn3b is expressed first, followed by Brn3a and Brn3c. Targeted deletion of Brn3b, but not Brn3a or Brn3c, leads to a loss of most retinal ganglion cells before birth. However, as a few retinal ganglion cells are still present in Brn3b(-/-) mice, Brn3a and Brn3c may partially compensate for the loss of Brn3b. To examine the role of Brn3c in retinal ganglion cell development, we generated Brn3b/Brn3c double knockout mice and analyzed their retinas and optic chiasms. Retinal ganglion cell axons from double knockout mice were more severely affected than were those from Brn3b-deficient mice, indicating that Brn3c was required for retinal ganglion cell differentiation and could partially compensate for the loss of Brn3b. Moreover, Brn3c had functions in retinal ganglion cell differentiation separate from those of Brn3b. Ipsilateral and misrouted projections at the optic chiasm were overproduced in Brn3b(-/-) mice but missing were entirely in optic chiasms of Brn3b/Brn3c double knockout mice, suggesting that Brn3c controlled ipsilateral axon production. Forced expression of Brn3c in Brn3b(-/-) retinal explants restored neurite outgrowth, demonstrating that Brn3c could promote axon outgrowth in the absence of Brn3b. Our results reveal a complex genetic relationship between Brn3b and Brn3c in regulating the retinal ganglion cell axon outgrowth.

Animals↗
PubMed2002

Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer.

Restoration of brain function by neural transplants is largely dependent upon the survival of donor neurons. Unfortunately, in both rodent models and human patients with Parkinson's disease the survival rate of transplanted neurons has been poor. We have employed a strategy to increase the availability of nutrients to the transplant by increasing the rate at which blood vessels are formed. Replication-deficient HSV-1 vectors containing the cDNA for human vascular endothelial growth factor (HSVhvegf) and the bacterial beta-galactosidase gene (HSVlac) have been transduced in parallel into nonadherent neuronal aggregate cultures made of cells from embryonic day 15 rat mesencephalon. Gene expression from HSVlac was confirmed in fixed preparations by staining with X-gal. VEGF expression as determined by sandwich ELISA assay of culture supernatant was up to 322-fold higher in HSVhvegf-infected than HSVlac-infected sister cultures. This peptide was also biologically active, inducing endothelial cell proliferation in vitro. Adult Sprague-Dawley rats received bilateral transplants into the striatum, with HSVlac on one side and HSVhvegf on the other. At defined intervals up to 8 weeks, animals were sacrificed and vibratome sections of the striatum were assessed for various parameters of cell survival and vascularization. Results demonstrate dose-dependent increases in blood vessel density within transplants transduced with HSVhvegf. These transplants were vascularized at a faster rate up to 4 weeks after transplantation. After 8 weeks, the average size of the HSVhvegf-infected transplants was twice that of controls. In particular, the survival of transplanted dopaminergic neurons increased 3.9-fold. Taken together these experiments provide convincing evidence that the rate of vascularization may be a major determinant of neuronal survival that can be manipulated by VEGF gene transduction.

Animals↗
PubMedDate not supplied

Somatic mosaic approaches and the aging brain.

Elucidating the function of neural pathways in the aging mammalian brain is a formidable task. Mechanisms that underlie aging and pathogenesis in specific brain circuits have been particularly elusive. However, animal models have been exploited in studies related to normative and pathogenic aging. Traditional transgenic animals represent permanent germ-line alterations in gene expression; changes that are present during development, remain indefinitely and likely invoke compensatory changes in the animal. In contrast, conditional transgenic animals combined with somatic gene delivery afford precise temporal and spatial gene regulation. In this review, we will detail current somatic mosaic approaches to study networks involved in the recognition, interpretation and recall of spatial representations, the septohippocampal pathway. We will also highlight potential uses for this approach in Alzheimer's disease, a complex pathophysiological state involving changes in many cellular pathways.

Aging↗
PubMedDate not supplied

Current treatment for Alzheimer disease and future prospects.

A cascade of pathophysiological events is triggered in Alzheimer disease (AD) that ultimately involves common cellular signaling pathways and leads to cellular and network dysfunction, failure of neurotransmission, cell death, and a common clinical outcome. The process is asynchronous, meaning that viable neurons remain as targets for therapy even in the diseased state, and each stage of the cascade affords the possibility for therapeutic intervention. Cholinesterase inhibitors are the only available treatment in the United States for patients with mild to moderate AD, helping maintain cognitive and functional abilities in most patients and conferring beneficial behavioral effects in some. Memantine is an NMDA receptor antagonist that has recently been approved in Europe for treatment of moderately severe to severe AD and is under investigation in the United States. Its mechanism of action may include enhanced neurotransmission in several systems as well as antiexcitotoxic effects. There are data regarding the effectiveness of the combination of memantine with cholinesterase inhibitors that will be useful for the practicing clinician. Other agents have shown some benefit in clinical trials, including the antioxidants vitamin E, selegiline, and Ginkgo biloba extracts, although the weight of evidence regarding their effects is not sufficient to define clinical practice. Potential future therapies currently are in development that target multiple aspects of the illness cascade, including aberrant inflammation, neurotrophic function, and processing of beta amyloid and tau proteins. These newer approaches hold promise for disease modification but are as yet unproven. Whether or not disease-modifying or preventive therapies become a reality, clinicians will be faced with AD patients who require treatment at all stages of illness for the indefinite future. Cholinergic and emerging noncholinergic medications will likely prevail as the standards of treatment for years to come.

Alzheimer Disease↗