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Stradleigh T.W.,University of California at Davis | Greenberg K.P.,University of California at Berkeley | Greenberg K.P.,Eos Neuroscience, Inc. | Partida G.J.,University of California at Davis | And 3 more authors.
Journal of Comparative Neurology | Year: 2015

Protocols for characterizing cellular phenotypes commonly use chemical fixatives to preserve anatomical features, mechanically stabilize tissue, and stop physiological responses. Formaldehyde, diluted in either phosphate-buffered saline or phosphate buffer, has been widely used in studies of neurons, especially in conjunction with dyes and antibodies. However, previous studies have found that these fixatives induce the formation of bead-like varicosities in the dendrites and axons of brain and spinal cord neurons. We report here that these formaldehyde formulations can induce bead formation in the dendrites and axons of adult rat and rabbit retinal ganglion cells, and that retinal ganglion cells differ from hippocampal, cortical, cerebellar, and spinal cord neurons in that bead formation is not blocked by glutamate receptor antagonists, a voltage-gated Na+ channel toxin, extracellular Ca2+ ion exclusion, or temperature shifts. Moreover, we describe a modification of formaldehyde-based fixatives that prevents bead formation in retinal ganglion cells visualized by green fluorescent protein expression and by immunohistochemistry. © 2014 Wiley Periodicals, Inc.


Patent
Eos Neuroscience, Inc. and Foundation University | Date: 2014-06-06

Provided herein are compositions and methods for gene and etiology-nonspecific and circuit-specific treatment of diseases, utilizing vectors for delivery of light-sensitive proteins to diseased and normal cells and tissues of interest.


Patent
Foundation University and Eos Neuroscience, Inc. | Date: 2015-08-26

Provided herein are compositions and methods for gene and etiology-nonspecific and circuit- specific treatment of diseases, utilizing vectors for delivery of light-sensitive proteins to diseased and normal cells and tissues of interest.


Doroudchi M.M.,Eos Neuroscience, Inc. | Greenberg K.P.,Eos Neuroscience, Inc. | Greenberg K.P.,University of California at Berkeley | Liu J.,University of Florida | And 14 more authors.
Molecular Therapy | Year: 2011

Previous work established retinal expression of channelrhodopsin-2 (ChR2), an algal cation channel gated by light, restored physiological and behavioral visual responses in otherwise blind rd1 mice. However, a viable ChR2-based human therapy must meet several key criteria: (i) ChR2 expression must be targeted, robust, and long-term, (ii) ChR2 must provide long-term and continuous therapeutic efficacy, and (iii) both viral vector delivery and ChR2 expression must be safe. Here, we demonstrate the development of a clinically relevant therapy for late stage retinal degeneration using ChR2. We achieved specific and stable expression of ChR2 in ON bipolar cells using a recombinant adeno-associated viral vector (rAAV) packaged in a tyrosine-mutated capsid. Targeted expression led to ChR2-driven electrophysiological ON responses in postsynaptic retinal ganglion cells and significant improvement in visually guided behavior for multiple models of blindness up to 10 months postinjection. Light levels to elicit visually guided behavioral responses were within the physiological range of cone photoreceptors. Finally, chronic ChR2 expression was nontoxic, with transgene biodistribution limited to the eye. No measurable immune or inflammatory response was observed following intraocular vector administration. Together, these data indicate that virally delivered ChR2 can provide a viable and efficacious clinical therapy for photoreceptor disease-related blindness. © The American Society of Gene & Cell Therapy.


Nanduri D.,University of Southern California | Nanduri D.,Doheny Eye Institute | Fine I.,University of Southern California | Horsager A.,University of Washington | And 7 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

PURPOSE. In an effort to restore functional form vision, epiretinal prostheses that elicit percepts by directly stimulating remaining retinal circuitry were implanted in human subjects with advanced retinitis pigmentosa RP). In this study, manipulating pulse train frequency and amplitude had different effects on the size and brightness of phosphene appearance. METHODS. Experiments were performed on a single subject with severe RP (implanted with a 16-channel epiretinal prosthesis in 2004) on nine individual electrodes. Psychophysical techniques were used to measure both the brightness and size of phosphenes when the biphasic pulse train was varied by either modulating the current amplitude (with constant frequency) or the stimulating frequency (with constant current amplitude). RESULTS. Increasing stimulation frequency always increased brightness, while having a smaller effect on the size of elicited phosphenes. In contrast, increasing stimulation amplitude generally increased both the size and brightness of phosphenes. These experimental findings can be explained by using a simple computational model based on previous psychophysical work and the expected spatial spread of current from a disc electrode. CONCLUSIONS. Given that amplitude and frequency have separable effects on percept size, these findings suggest that frequency modulation improves the encoding of a wide range of brightness levels without a loss of spatial resolution. Future retinal prosthesis designs could benefit from having the flexibility to manipulate pulse train amplitude and frequency independently. © 2012 The Association for Research in Vision and Ophthalmology, Inc.


Uren P.J.,University of Southern California | Lee J.T.,University of Southern California | Mehdi Doroudchi M.,Eos Neuroscience, Inc. | Smith A.D.,University of Southern California | Horsager A.,University of Southern California
Molecular Vision | Year: 2014

Purpose: Retinitis pigmentosa (RP) is a photoreceptor disease that affects approximately 100,000 people in the United States. Treatment options are limited, and the prognosis for most patients is progressive vision loss. Unfortunately, understanding of the molecular underpinnings of RP initiation and progression is still limited. However, the development of animal models of RP, coupled with high-throughput sequencing, has provided an opportunity to study the underlying cellular and molecular changes in this disease.Methods: Using RNA-Seq, we present the frst retinal transcriptome analysis of the rd10 murine model of retinal degeneration.Results: Our data confrm the loss of rod-specifc transcripts and the increased relative expression of Müller-specifc transcripts, emphasizing the important role of reactive gliosis and innate immune activation in R P. Moreover, we report substantial changes in relative isoform usage among neuronal differentiation and morphogenesis genes, including a marked shift to shorter transcripts.Conclusions: Our analyses implicate remodeling of the inner retina and possible Müller cell dedifferentiation. © 2014 Molecular Vision.


Doroudchi M.M.,Eos Neuroscience, Inc.
Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference | Year: 2011

Over the last several years we have developed a rapidly-expanding suite of genetically-encoded reagents (e.g., ChR2, Halo, Arch, Mac, and others) that, when expressed in specific neuron types in the nervous system, enable their activities to be powerfully and precisely activated and silenced in response to light. If the genes that encode for these reagents can be delivered to cells in the body using gene therapy methods, and if the resultant protein payloads operate safely and effectively over therapeutically important periods of time, these molecules could subserve a set of precise prosthetics that use light as the trigger of information entry into the nervous system, e.g. for sensory replacement. Here we discuss the use of ChR2 to make the photoreceptor-deprived retina, as found in diseases such as retinitis pigmentosa, sensitive to light, enabling restoration of functional vision in a mouse model of blindness. We also discuss arrays of light sources that could be useful for delivering patterned sensory information into the nervous system.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 394.44K | Year: 2011

DESCRIPTION (provided by applicant): Eos Neuroscience, Inc., in collaboration with the company's academic partners, is developing a novel technology combining gene therapeutics and optical neuromodulation techniques to enable a potential therapy for neuropathic pain. It is the hope of our company that this technology will be widely applicable and available to individuals in the United States and worldwide that suffer from debilitating chronic pain. In brief, Eos Neuroscience, Inc. is creating a technology that will restore inhibition to hyperactive neurons in the dorsal root ganglion (DRG) with fiber optic illumination. To this end, we are developing a targeted delivery mechanism using an adeno-associated virus (AAV) that is proven effective at delivering genes into DRG. We will use this mechanism to target a photosensitive inhibitory proton pump, into the nociceptive DRG neurons and study the immunohistochemical localization of our transgene and physiology of these transduced DRG. The goal of this Phase I project is to characterize the targeting efficiency and specificity with which we can deliver our transgene to nociceptive DRG neurons using ubiquitous and cell specific promoters. We will then perform electrophysiology to characterize the light driven inhibitory responses in transduced DRG neurons to determine the efficacy with which we can silence spontaneous hyperactivity. We have started this testing in rats and will continue to evaluate both vector targeting and physiological measures. Accordingly, we propose the following specific aims for our SBIR Phase I project: 1) Design and construct AAV vectors using well-characterized promoters, for specific expression of an optical silencer in nociceptive neurons of the DRG, 2) Deliver AAV vectors via intrathecalinjection to rodent DRG and evaluate targeting specificity and toxicity via Immunohistochemistry, and 3) Characterize the optical silencing capability of these AAV vectors in DRG using cell attached and whole cell intracellular recording. We are very enthusiastic that results obtained from this Phase I study will enable us to submit a Phase II with the eventual goal of a clinical therapeutic product. PUBLIC HEALTH RELEVANCE: Pain is a major health problem, with 290 million people suffering worldwideand 86 million in the US. Current therapeutic approaches (e.g., pharmacological, surgical, electrical stimulation and physical rehabilitation therapy) generally fail to target pain pathways selectively, resulting in undesired side effects that can significantly impair physical and mental ability and may include central nervous system depression, cognitive dysfunction, blockade of motor neurons, and weakness. To this end, Eos Neuroscience, Inc. and academic partners will establish a gene therapy based technology that can be applied broadly using a light sensitive protein to silence pain sensation directly in sensory neurons of patients suffering from chronic pain.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 295.77K | Year: 2012

DESCRIPTION (provided by applicant): Eos Neuroscience, Inc., in collaboration with its academic partners, is developing a novel technology combining gene therapeutics and optical engineering techniques to restore functional vision to individuals that are blind from photoreceptor related diseases such as Retinitis Pigmentosa or Age-Related Macular Degeneration. We believe that this technology will be widely applicable to the general public, in the United States and worldwide, which suffers from these debilitating and blinding diseases. In brief, Eos Neuroscience, Inc. is creating a technology that will restore photosensitivity in the remaining cells of the retina after the photoreceptors have died or are no longer functional, thus restoring the ability of theretina to respond to light stimulation. To this end, we have created a delivery mechanism using an adeno-associated virus (AAV) that is proven safe and effective at delivering genes into cells. We will use this mechanism to express light-sensitive proteins into the spared, functioning cells of the retina. Additionally, we are completing the remaining required safety and efficacy studies necessary to gain preclinical readiness. In the course of our Phase I funding/operating period, we completed studies toevaluate both physiological and behavioral efficacy measures in murine models of retinal degeneration. Here, we will attempt to further improve our therapeutic vector by employing more sensitive opsins and evaluate the efficacy of these opsins through physiological and behavioral measures. PUBLIC HEALTH RELEVANCE: Photoreceptor diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are leading causes of blindness, affecting approximately 15 million people worldwide. Current therapies are targeting single genetic defects or are using electrical stimulation to restore visual function - neither of which is capabl of being a treatment that can be applied broadly to photoreceptor disease. To this end, Eos Neuroscience, Inc.has established a technology using genetically expressed light sensitive proteins to restore light sensitivity in patients suffering from photoreceptor degeneration, a technology that can be applied broadly and accurately for the treatment of these diseases.


Patent
Eos Neuroscience, Inc. | Date: 2011-10-14

Provided herein are compositions and methods for the design of synthetic regulatory sequences and for subsequent modulation of neural pathways.

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