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Weng Tao - One of the best experts on this subject based on the ideXlab platform.
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Encapsulated Cell-Based Intraocular Delivery of Ciliary Neurotrophic Factor in Normal Rabbit: Dose-Dependent Effects on ERG and Retinal Histology
2020Co-Authors: Weng Tao, Paul A Sieving, Bo Lei, Dorit Raz, Chi-chao Chan, Terry A Cox, Maria Santos-muffley, Ronald A BushAbstract:PURPOSE. ERG and histologic changes were investigated in normal rabbits after intravitreal implantation of Encapsulated Cell technology (ECT) devices releasing ciliary neurotrophic factor (CNTF). METHODS. Fifteen adult New Zealand White albino rabbits had ECT devices secreting CNTF at 22, 5, or 0 ng/d implanted in the superior temporal quadrant of the left eye. The low dose has been shown to produce substantial rescue of photoreceptors in the rcd1 canine model of retinal degeneration. Right eyes were untreated. Ganzfeld dark-and light-adapted ERGs and clinical observations were performed at 5, 15, and 25 days after implantation. Rod a-waves and rod and cone b-waves and outer nuclear layer (ONL) morphology were evaluated at 25 days. RESULTS. Clinical examination showed minimal changes in a few CNTF-treated eyes, including vitreous membranes and engorgement of iris vessels at day 25. Retinas appeared normal. CNTF did not significantly affect the rod a-or b-waves, although the b-wave amplitude tended to be larger in CNTFtreated retinas at low flash intensities. The cone b-wave amplitude was significantly reduced in high-dose eyes at some flash intensities. The ONL area in high-dose eyes was significantly greater because of increased thickness than in fellow retinas. ONL Cell size was significantly increased, and staining density decreased in CNTF-treated retinas. CONCLUSIONS. CNTF, given by intravitreal ECT device at doses that protect photoreceptors in a canine model of retinal degeneration (5 ng/d), did not adversely affect either rod or cone ERG function of normal rabbit retina. The cone ERG was more sensitive to suppression being reduced, at low flash intensities, by 22 ng/d. Dose-related changes in the ONL and photoreceptor Cell nuclei did not represent a toxic effect, because they were not associated with deficits in the rod ERG over a broad range of intensities. (Invest Ophthalmol Vis Sci. 2004;45: 2420 -2430 5 which showed a significant preservation of the a-and b-waves of the scotopic ERG in the retinal degeneration slow (rds) mouse after adenovirus-mediated delivery. 5 Unfortunately, it is difficult to regulate the level and the site of CNTF expression with viral gene transfer techniques. The vector delivers the gene to a number of Cell types, and the gene product is expressed intraCellularly rather than interacting with receptors on the external Cell membrane. In addition, several of the previous studies were suspected of delivering toxic dose levels of CNTF. Encapsulated Cell technology (ECT) provides extraCellular delivery of CNTF through continual and stable intraocular release at known doses through a device implanted in the vitreous chamber. CNTF delivered by ECT produced dosedependent photoreceptor rescue in the rcd1 canine model of retinal degeneration, 9 but retinal function was not evaluated in that study. We implanted ECT devices releasing CNTF in the eyes of normal rabbits to study the effects of exogenous CNTF, at appropriate therapeutic dose levels, on normal retinal function. Because previous studies have shown morphologic changes in the outer nuclear layer (ONL) related to CNTF gene transfer
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ciliary neurotrophic factor for macular telangiectasia type 2 results from a phase 1 safety trial
American Journal of Ophthalmology, 2015Co-Authors: Emily Y Chew, Traci E Clemons, Weng Tao, Tunde Peto, Ferenc B Sallo, Avner Ingerman, Lawrence J Singerman, Steven D Schwartz, Neal S PeacheyAbstract:Purpose To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an Encapsulated Cell implant for the treatment of macular telangiectasia type 2. Design An open-label safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. Methods The participant's more severely affected eye (worse baseline visual acuity) received the high-dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. Results The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. Conclusions The intraocular delivery of CNTF in the Encapsulated Cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy.
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ciliary neurotrophic factor delivered by Encapsulated Cell intraocular implants for treatment of geographic atrophy in age related macular degeneration
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Kang Zhang, David G Birch, Glenn J Jaffe, Weng Tao, Jill J Hopkins, Jeffrey S Heier, Lawrence Halperin, Thomas A Albini, David M Brown, George A WilliamsAbstract:Abstract There is no treatment available for vision loss associated with advanced dry age-related macular degeneration (AMD) or geographic atrophy (GA). In a pilot, proof of concept phase 2 study, we evaluated ciliary neurotrophic factor (CNTF) delivered via an intraocular Encapsulated Cell technology implant for the treatment of GA. We designed a multicenter, 1-y, double-masked, sham-controlled dose-ranging study. Patients with GA were randomly assigned to receive a high-or low-dose implant or sham surgery. The primary endpoint was the change in best corrected visual acuity (BCVA) at 12 mo. CNTF treatment resulted in a dose-dependent increase in retinal thickness. This change was followed by visual acuity stabilization (loss of less than 15 letters) in the high-dose group (96.3%) compared with low-dose (83.3%) and sham (75%) group. A subgroup analysis of those with baseline BCVA at 20/63 or better revealed that 100% of patients in the high-dose group lost <15 letters compared with 55.6% in the combined low-dose/sham group (P = 0.033). There was a 0.8 mean letter gain in the high-dose group compared with a 9.7 mean letter loss in the combined low-dose/sham group (P = 0.0315). Both the implant and the implant procedure were well-tolerated. These findings suggest that CNTF delivered by the Encapsulated Cell technology implant appears to slow the progression of vision loss in GA, especially in eyes with 20/63 or better vision at baseline.
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application of Encapsulated Cell technology for retinal degenerative diseases
Expert Opinion on Biological Therapy, 2006Co-Authors: Weng TaoAbstract:Ophthalmic disorders represent a rapidly growing disease area that is associated with the ageing population. Their sight is threatened by age-related macular degeneration, diabetic retinopathy, glaucoma and/or retinitis pigmentosa (RP). Few effective treatments for these disorders are available at present, in part due to lack of effective delivery of therapeutic molecules to the retina. Encapsulated Cell technology (ECT) allows the controlled, continuous and long-term administration of protein drugs in the eye, where therapeutic agents are needed, and does not subject the host to the systemic exposure. Furthermore, the implants can be retrieved, providing an added level of safety. Ciliary neurotrophic factor (CNTF) has been shown to protect the retina from degeneration in 13 animal models, and ECT-based delivery of CNTF protected photoreceptors in the rcd1 dog model of RP.
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ciliary neurotrophic factor cntf for human retinal degeneration phase i trial of cntf delivered by Encapsulated Cell intraocular implants
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Paul A Sieving, Weng Tao, Rafael C Caruso, Hanna R Coleman, Darby J S Thompson, Keri R Fullmer, Ronald A BushAbstract:Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by Cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the Encapsulated Cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable Cells with minimal Cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10–15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using Encapsulated Cell implants may have application beyond disease caused by genetic mutations.
Patrick Aebischer - One of the best experts on this subject based on the ideXlab platform.
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a subcutaneous Cellular implant for passive immunization against amyloid β reduces brain amyloid and tau pathologies
Brain, 2016Co-Authors: Aurelien Lathuiliere, Vanessa Laversenne, Alberto Astolfo, Erhard Kopetzki, Helmut Jacobsen, Marco Stampanoni, Bernd Bohrmann, Bernard L Schneider, Patrick AebischerAbstract:Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer’s disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive Cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic Cells over more than 10 months in immunocompetent allogeneic recipients. The Encapsulated Cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer’s pathology. When Encapsulated Cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of Encapsulated Cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer’s disease and other neurodegenerative disorders. * Abbreviations : ECT : Encapsulated Cell technology mAb : monoclonal antibody
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immunoisolated xenogenic chromaffin Cell therapy for chronic pain initial clinical experience
Anesthesiology, 1996Co-Authors: E Buchser, Moses Goddard, B Heyd, Jeanmarc Joseph, Jacques Favre, N De Tribolet, M Lysaght, Patrick AebischerAbstract:BACKGROUND: Chromaffin Cells from the adrenal gland secrete a mixture of compounds that have a strong analgesic effect, especially when administered intrathecally. Many studies in animal models have shown that discordant xenogeneic Cell isolates, including chromaffin Cells, can survive and have biologic effects when transplanted within a semipermeable membrane capsule. METHODS: To evaluate the clinical potential of Encapsulated Cell therapy, a human-scale implant containing bovine chromaffin Cells was developed, characterized, and implanted in the subarachnoid space of seven patients with severe chronic pain not satisfactorily managed with conventional therapies. Patients received no pharmacologic immunosuppression. Cell devices were implanted during minimally invasive surgery, and device design allowed retrieval. All devices were recovered after implant periods of 41 to 176 days. RESULTS: Postexplant histologic analysis, immunostaining, and secretory function all confirmed survival and biochemical function of the Encapsulated Cells. Reductions in morphine intake and improvement in pain ratings were observed in several patients. CONCLUSIONS: This study represents the first successful trial of Encapsulated xenogeneic Cells in humans. The preliminary findings of pain reduction warrant the initiation of a randomized, double-blind phase II study to evaluate the potential efficacy of the procedure.
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polymer Encapsulated Cell lines genetically engineered to release ciliary neurotrophic factor can slow down progressive motor neuronopathy in the mouse
European Journal of Neuroscience, 1995Co-Authors: Y Sagot, S A Tan, E Baetge, H Schmalbruch, A C Kato, Patrick AebischerAbstract:Ciliary neurotrophic factor (CNTF) has recently generated great interest due to its potential as a therapeutic agent for the treatment of human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Because the systemic half-life of CNTF is only in the order of a few minutes, continuous delivery of this trophic factor could be attractive or even necessary in the therapy of these diseases. One promising technique involves the polymer encapsulation of Cells which have been genetically modified to secrete neurotrophic factors. The polymer capsules can be implanted into animals and effect the slow release of the protein for several months. The encapsulation technique immuno-isolates the foreign Cells from host immune Cells and at the same time prevents tumour formation by the transplanted Cells. In this study, we have used progressive motoneuronopathy (pmn) mice to determine the extent to which Encapsulated Cell lines secreting CNTF could alter the course of the disease. pmn/pmn homozygotes present severe loss of myelinated motor fibres and a significant reduction of facial motoneuron Cell bodies. The mice develop weakness of the hindlimbs and die during the sixth week after birth. We found that CNTF delayed the disease progression by increasing the survival time by 40% and by improving motor function as assessed by three behavioural tests. Moreover, histological counts of the phrenic nerve myelinated axons and facial nucleus motoneurons indicated a significant reduction of motoneuron loss. These results suggest that polymer-Encapsulated Cells releasing neurotrophic factors may provide a potential delivery system for treating neurodegenerative diseases such as ALS.
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transplantation of a polymer Encapsulated Cell line genetically engineered to release ngf
Experimental Neurology, 1993Co-Authors: Diane Hoffman, Xandra O Breakefield, Priscilla M Short, Patrick AebischerAbstract:The delivery of nerve growth factor (NGF) to the lateral ventricle of a fimbria-fornix-lesioned rat prevents the lesion-induced reduction in choline acetyltransferase (ChAT) expression by medial septal Cells. Although delivery has been achieved through neural grafting of genetically engineered Cell lines which release NGF, transplanted Cells have grown beyond the implantation site and formed tumors. The encapsulation of Cells within a permselective polymer capsule prior to transplantation allows Cell growth only within the capsule space, while allowing molecular exchange between the host tissue and enclosed Cells. Rat fibroblasts from the parent Cell line (R208F) or fibroblasts genetically modified to produce NGF (R208N.8) were loaded within a thermoplastic hollow fiber-based capsule. Only the capsules loaded with the genetically engineered Cells released measurable amounts of NGF in culture. Adult rats received unilateral aspirative fimbria-fornix lesions, followed by intraventricular implantation of a R208F capsule (n = 6) or a R208N.8 capsule (n = 6). After 2 weeks, rats receiving Encapsulated Cells showed no undue reaction to the implants. With both Cell types, the Cells remained viable and confined to the capsule space. R208N.8 capsules released sufficient NGF to prevent the lesion-induced loss of septal ChAT expression, whereas R208F capsules did not. This study suggests that Encapsulated genetically engineered Cells can provide an efficient means for future applications involving delivery of neurotrophic factors.
Paul A Sieving - One of the best experts on this subject based on the ideXlab platform.
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Encapsulated Cell-Based Intraocular Delivery of Ciliary Neurotrophic Factor in Normal Rabbit: Dose-Dependent Effects on ERG and Retinal Histology
2020Co-Authors: Weng Tao, Paul A Sieving, Bo Lei, Dorit Raz, Chi-chao Chan, Terry A Cox, Maria Santos-muffley, Ronald A BushAbstract:PURPOSE. ERG and histologic changes were investigated in normal rabbits after intravitreal implantation of Encapsulated Cell technology (ECT) devices releasing ciliary neurotrophic factor (CNTF). METHODS. Fifteen adult New Zealand White albino rabbits had ECT devices secreting CNTF at 22, 5, or 0 ng/d implanted in the superior temporal quadrant of the left eye. The low dose has been shown to produce substantial rescue of photoreceptors in the rcd1 canine model of retinal degeneration. Right eyes were untreated. Ganzfeld dark-and light-adapted ERGs and clinical observations were performed at 5, 15, and 25 days after implantation. Rod a-waves and rod and cone b-waves and outer nuclear layer (ONL) morphology were evaluated at 25 days. RESULTS. Clinical examination showed minimal changes in a few CNTF-treated eyes, including vitreous membranes and engorgement of iris vessels at day 25. Retinas appeared normal. CNTF did not significantly affect the rod a-or b-waves, although the b-wave amplitude tended to be larger in CNTFtreated retinas at low flash intensities. The cone b-wave amplitude was significantly reduced in high-dose eyes at some flash intensities. The ONL area in high-dose eyes was significantly greater because of increased thickness than in fellow retinas. ONL Cell size was significantly increased, and staining density decreased in CNTF-treated retinas. CONCLUSIONS. CNTF, given by intravitreal ECT device at doses that protect photoreceptors in a canine model of retinal degeneration (5 ng/d), did not adversely affect either rod or cone ERG function of normal rabbit retina. The cone ERG was more sensitive to suppression being reduced, at low flash intensities, by 22 ng/d. Dose-related changes in the ONL and photoreceptor Cell nuclei did not represent a toxic effect, because they were not associated with deficits in the rod ERG over a broad range of intensities. (Invest Ophthalmol Vis Sci. 2004;45: 2420 -2430 5 which showed a significant preservation of the a-and b-waves of the scotopic ERG in the retinal degeneration slow (rds) mouse after adenovirus-mediated delivery. 5 Unfortunately, it is difficult to regulate the level and the site of CNTF expression with viral gene transfer techniques. The vector delivers the gene to a number of Cell types, and the gene product is expressed intraCellularly rather than interacting with receptors on the external Cell membrane. In addition, several of the previous studies were suspected of delivering toxic dose levels of CNTF. Encapsulated Cell technology (ECT) provides extraCellular delivery of CNTF through continual and stable intraocular release at known doses through a device implanted in the vitreous chamber. CNTF delivered by ECT produced dosedependent photoreceptor rescue in the rcd1 canine model of retinal degeneration, 9 but retinal function was not evaluated in that study. We implanted ECT devices releasing CNTF in the eyes of normal rabbits to study the effects of exogenous CNTF, at appropriate therapeutic dose levels, on normal retinal function. Because previous studies have shown morphologic changes in the outer nuclear layer (ONL) related to CNTF gene transfer
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ciliary neurotrophic factor cntf for human retinal degeneration phase i trial of cntf delivered by Encapsulated Cell intraocular implants
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Paul A Sieving, Weng Tao, Rafael C Caruso, Hanna R Coleman, Darby J S Thompson, Keri R Fullmer, Ronald A BushAbstract:Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by Cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the Encapsulated Cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable Cells with minimal Cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10–15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using Encapsulated Cell implants may have application beyond disease caused by genetic mutations.
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Encapsulated Cell based intraocular delivery of ciliary neurotrophic factor in normal rabbit dose dependent effects on erg and retinal histology
Investigative Ophthalmology & Visual Science, 2004Co-Authors: Ronald A Bush, Weng Tao, Paul A Sieving, Bo Lei, Dorit Raz, Chi-chao Chan, Terry A Cox, Maria SantosmuffleyAbstract:PURPOSE. ERG and histologic changes were investigated in normal rabbits after intravitreal implantation of Encapsulated Cell technology (ECT) devices releasing ciliary neurotrophic factor (CNTF). METHODS. Fifteen adult New Zealand White albino rabbits had ECT devices secreting CNTF at 22, 5, or 0 ng/d implanted in the superior temporal quadrant of the left eye. The low dose has been shown to produce substantial rescue of photoreceptors in the rcd1 canine model of retinal degeneration. Right eyes were untreated. Ganzfeld dark- and light-adapted ERGs and clinical observations were performed at 5, 15, and 25 days after implantation. Rod a-waves and rod and cone b-waves and outer nuclear layer (ONL) morphology were evaluated at 25 days. RESULTS. Clinical examination showed minimal changes in a few CNTF-treated eyes, including vitreous membranes and engorgement of iris vessels at day 25. Retinas appeared normal. CNTF did not significantly affect the rod a- or b-waves, although the b-wave amplitude tended to be larger in CNTF-treated retinas at low flash intensities. The cone b-wave amplitude was significantly reduced in high-dose eyes at some flash intensities. The ONL area in high-dose eyes was significantly greater because of increased thickness than in fellow retinas. ONL Cell size was significantly increased, and staining density decreased in CNTF-treated retinas. CONCLUSIONS. CNTF, given by intravitreal ECT device at doses that protect photoreceptors in a canine model of retinal degeneration (5 ng/d), did not adversely affect either rod or cone ERG function of normal rabbit retina. The cone ERG was more sensitive to suppression being reduced, at low flash intensities, by 22 ng/d. Dose-related changes in the ONL and photoreceptor Cell nuclei did not represent a toxic effect, because they were not associated with deficits in the rod ERG over a broad range of intensities.
Lars Wahlberg - One of the best experts on this subject based on the ideXlab platform.
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Unilateral ex vivo gene therapy by GDNF in epileptic rats
Gene Therapy, 2019Co-Authors: Avtandil Nanobashvili, Jens Tornoe, Lars Wahlberg, Esbjörn Melin, Dwaine Emerich, Michele Simonato, Merab KokaiaAbstract:Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults. This neurological disorder is characterized by focal seizures originating in the temporal lobe, often with secondary generalization. A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the epilepsy patients. Thus, developing more targeted and effective treatment strategies for focal seizures, originating from, e.g., the temporal lobe, is highly warranted. In order to deliver potential anti-epileptic agents directly into the seizure focus we used Encapsulated Cell biodelivery (ECB), a specific type of ex vivo gene therapy. Specifically, we asked whether unilateral delivery of glial Cell line-derived neurotrophic factor (GDNF), exclusively into the epileptic focus, would suppress already established spontaneous recurrent seizures (SRS) in rats. Our results show that GDNF delivered by ECB devices unilaterally into the seizure focus in the hippocampus effectively decreases the number of SRS in epileptic rats. Thus, our study demonstrates that focal unilateral delivery of neurotrophic factors, such as GDNF, using ex vivo gene therapy based on ECB devices could be an effective anti-epileptic strategy providing a bases for the development of a novel, alternative, treatment for focal epilepsies.
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targeted delivery of nerve growth factor via Encapsulated Cell biodelivery in alzheimer disease a technology platform for restorative neurosurgery
Journal of Neurosurgery, 2012Co-Authors: Lars Wahlberg, Jens Tornoe, Philip Kusk, Bengt Juliusson, Goran Lind, Per Almqvist, Michael Soderman, Eva Sellden, Ake Seiger, Maria EriksdotterjonhagenAbstract:Object The authors describe the first clinical trial with Encapsulated Cell biodelivery (ECB) implants that deliver nerve growth factor (NGF) to the cholinergic basal forebrain with the intention of halting the degeneration of cholinergic neurons and the associated cognitive decline in patients with Alzheimer disease (AD). The NsG0202 implant (NsGene A/S) consists of an NGF-producing, genetically engineered human Cell line Encapsulated behind a semipermeable hollow fiber membrane that allows the influx of nutrients and the efflux of NGF. The centimeter-long capsule is attached to an inert polymer tether that is used to guide the capsule to the target via stereotactic techniques and is anchored to the skull at the bur hole. Methods Six patients with mild to moderate AD were included in this Phase Ib open-label safety study and were divided into 2 dose cohorts. The first cohort of 3 patients received single implants targeting the basal nucleus of Meynert (Ch4 region) bilaterally (2 implants per patient), an...
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long term delivery of nerve growth factor by Encapsulated Cell biodelivery in the gottingen minipig basal forebrain
Molecular Therapy, 2010Co-Authors: Lone Fjordlarsen, Carsten R. Bjarkam, Jens Tornoe, Jens Christian Sorensen, Philip Kusk, Bengt Juliusson, Malene Torp, Mette S Nielsen, Aase Handberg, Lars WahlbergAbstract:Nerve growth factor (NGF) prevents cholinergic degeneration in Alzheimer's disease (AD) and improves memory in AD animal models. In humans, the safe delivery of therapeutic doses of NGF is challenging. For clinical use, we have therefore developed an Encapsulated Cell (EC) biodelivery device, capable of local delivery of NGF. The clinical device, named NsG0202, houses an NGF-secreting Cell line (NGC-0295), which is derived from a human retinal pigment epithelial (RPE) Cell line, stably genetically modified to secrete NGF. Bioactivity and correct processing of NGF was confirmed in vitro. NsG0202 devices were implanted in the basal forebrain of Gottingen minipigs and the function and retrievability were evaluated after 7 weeks, 6 and 12 months. All devices were implanted and retrieved without associated complications. They were physically intact and contained a high number of viable and NGF-producing NGC-0295 Cells after explantation. Increased NGF levels were detected in tissue surrounding the devices. The implants were well tolerated as determined by histopathological brain tissue analysis, blood analysis, and general health status of the pigs. The NsG0202 device represents a promising approach for treating the cognitive decline in AD patients.
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Encapsulated Cell biodelivery of gdnf a novel clinical strategy for neuroprotection and neuroregeneration in parkinson s disease
Experimental Neurology, 2008Co-Authors: Olle Lindvall, Lars WahlbergAbstract:The main pathology underlying disease symptoms in Parkinson's disease (PD) is a progressive degeneration of nigrostriatal dopamine (DA) neurons. No effective disease-modifying treatment currently exists. Glial Cell line-derived neurotrophic factor (GDNF) has neuroprotective and neuroregenerative effects and it enhances dopaminergic function in animal models of PD. These findings raise the possibility that intrastriatal administration of GDNF might be developed into a new clinical strategy for functional preservation and restoration also in PD patients. Gene therapy is a novel tool to increase local levels of GDNF. Transplantation of Encapsulated, GDNF-secreting Cells is one strategy for ex vivo Cell-based gene delivery which has the advantage to allow for removal of the Cells if untoward effects occur. Here we summarize studies with such Cells in animals, and discuss the results from previous trials with GDNF in PD patients and their implications for the further development of neuroprotective/neuroregenerative therapies. Finally, we describe the different scientific and regulatory issues that need to be addressed in order to reach the clinic and start the first trial in patients.
Ronald A Bush - One of the best experts on this subject based on the ideXlab platform.
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Encapsulated Cell-Based Intraocular Delivery of Ciliary Neurotrophic Factor in Normal Rabbit: Dose-Dependent Effects on ERG and Retinal Histology
2020Co-Authors: Weng Tao, Paul A Sieving, Bo Lei, Dorit Raz, Chi-chao Chan, Terry A Cox, Maria Santos-muffley, Ronald A BushAbstract:PURPOSE. ERG and histologic changes were investigated in normal rabbits after intravitreal implantation of Encapsulated Cell technology (ECT) devices releasing ciliary neurotrophic factor (CNTF). METHODS. Fifteen adult New Zealand White albino rabbits had ECT devices secreting CNTF at 22, 5, or 0 ng/d implanted in the superior temporal quadrant of the left eye. The low dose has been shown to produce substantial rescue of photoreceptors in the rcd1 canine model of retinal degeneration. Right eyes were untreated. Ganzfeld dark-and light-adapted ERGs and clinical observations were performed at 5, 15, and 25 days after implantation. Rod a-waves and rod and cone b-waves and outer nuclear layer (ONL) morphology were evaluated at 25 days. RESULTS. Clinical examination showed minimal changes in a few CNTF-treated eyes, including vitreous membranes and engorgement of iris vessels at day 25. Retinas appeared normal. CNTF did not significantly affect the rod a-or b-waves, although the b-wave amplitude tended to be larger in CNTFtreated retinas at low flash intensities. The cone b-wave amplitude was significantly reduced in high-dose eyes at some flash intensities. The ONL area in high-dose eyes was significantly greater because of increased thickness than in fellow retinas. ONL Cell size was significantly increased, and staining density decreased in CNTF-treated retinas. CONCLUSIONS. CNTF, given by intravitreal ECT device at doses that protect photoreceptors in a canine model of retinal degeneration (5 ng/d), did not adversely affect either rod or cone ERG function of normal rabbit retina. The cone ERG was more sensitive to suppression being reduced, at low flash intensities, by 22 ng/d. Dose-related changes in the ONL and photoreceptor Cell nuclei did not represent a toxic effect, because they were not associated with deficits in the rod ERG over a broad range of intensities. (Invest Ophthalmol Vis Sci. 2004;45: 2420 -2430 5 which showed a significant preservation of the a-and b-waves of the scotopic ERG in the retinal degeneration slow (rds) mouse after adenovirus-mediated delivery. 5 Unfortunately, it is difficult to regulate the level and the site of CNTF expression with viral gene transfer techniques. The vector delivers the gene to a number of Cell types, and the gene product is expressed intraCellularly rather than interacting with receptors on the external Cell membrane. In addition, several of the previous studies were suspected of delivering toxic dose levels of CNTF. Encapsulated Cell technology (ECT) provides extraCellular delivery of CNTF through continual and stable intraocular release at known doses through a device implanted in the vitreous chamber. CNTF delivered by ECT produced dosedependent photoreceptor rescue in the rcd1 canine model of retinal degeneration, 9 but retinal function was not evaluated in that study. We implanted ECT devices releasing CNTF in the eyes of normal rabbits to study the effects of exogenous CNTF, at appropriate therapeutic dose levels, on normal retinal function. Because previous studies have shown morphologic changes in the outer nuclear layer (ONL) related to CNTF gene transfer
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ciliary neurotrophic factor cntf for human retinal degeneration phase i trial of cntf delivered by Encapsulated Cell intraocular implants
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Paul A Sieving, Weng Tao, Rafael C Caruso, Hanna R Coleman, Darby J S Thompson, Keri R Fullmer, Ronald A BushAbstract:Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by Cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the Encapsulated Cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable Cells with minimal Cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10–15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using Encapsulated Cell implants may have application beyond disease caused by genetic mutations.
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Encapsulated Cell based intraocular delivery of ciliary neurotrophic factor in normal rabbit dose dependent effects on erg and retinal histology
Investigative Ophthalmology & Visual Science, 2004Co-Authors: Ronald A Bush, Weng Tao, Paul A Sieving, Bo Lei, Dorit Raz, Chi-chao Chan, Terry A Cox, Maria SantosmuffleyAbstract:PURPOSE. ERG and histologic changes were investigated in normal rabbits after intravitreal implantation of Encapsulated Cell technology (ECT) devices releasing ciliary neurotrophic factor (CNTF). METHODS. Fifteen adult New Zealand White albino rabbits had ECT devices secreting CNTF at 22, 5, or 0 ng/d implanted in the superior temporal quadrant of the left eye. The low dose has been shown to produce substantial rescue of photoreceptors in the rcd1 canine model of retinal degeneration. Right eyes were untreated. Ganzfeld dark- and light-adapted ERGs and clinical observations were performed at 5, 15, and 25 days after implantation. Rod a-waves and rod and cone b-waves and outer nuclear layer (ONL) morphology were evaluated at 25 days. RESULTS. Clinical examination showed minimal changes in a few CNTF-treated eyes, including vitreous membranes and engorgement of iris vessels at day 25. Retinas appeared normal. CNTF did not significantly affect the rod a- or b-waves, although the b-wave amplitude tended to be larger in CNTF-treated retinas at low flash intensities. The cone b-wave amplitude was significantly reduced in high-dose eyes at some flash intensities. The ONL area in high-dose eyes was significantly greater because of increased thickness than in fellow retinas. ONL Cell size was significantly increased, and staining density decreased in CNTF-treated retinas. CONCLUSIONS. CNTF, given by intravitreal ECT device at doses that protect photoreceptors in a canine model of retinal degeneration (5 ng/d), did not adversely affect either rod or cone ERG function of normal rabbit retina. The cone ERG was more sensitive to suppression being reduced, at low flash intensities, by 22 ng/d. Dose-related changes in the ONL and photoreceptor Cell nuclei did not represent a toxic effect, because they were not associated with deficits in the rod ERG over a broad range of intensities.