Ginsburg Institute for Biomedical Therapeutics

NEURAL ELECTRONICS
Interface to Neurosensory System
As both an ophthalmologist and biomedical engineer, Dr. Mark Humayun works at the interface of engineering and medicine. Dr. Humayun and his colleague Dr. James Weiland assembled a team of world experts to create a revolutionary device, known as the Argus II retinal implant for those suffering from an inherited form of blindness called retinitis pigmentosa (RP). It is the world’s first FDA approved artificial retina system, which offers an unprecedented degree of sight to those with complete retinal blindness. The Argus II device is a 60 electrode retinal prosthesis that captures images by an eye glass mounted camera which sends wireless signals to the implanted chip. Once transmitted to the retina (light sensing and image processing part of the eye), the signal is carried to the optic nerve (the nerve connecting the eye to brain) and translated into an image.
Argus II – First FDA-Approved Retinal Prosthesis
The ophthalmic device is a retinal implant system that consists of an eyeglass mounted camera and an implanted 60 electrode retinal stimulator.
The stimulator, implanted on the eye and interfacing directly to the retina, relays signals from the external camera to the retina via small electrical impulses, which triggers signals in the retina that are passed to the brain via the optic nerve.
The brain is then able to process the signals into a visual picture.
Brain Injury-Effects on Neurosensory System and Cognition
One of the IBT initiatives is to restore higher cognitive functions that are lost as a result of damage (stroke, head trauma, epilepsy) or degenerative disease (dementia, Alzheimer’s disease) through developing a neural prosthesis. Specifically, we are focusing on loss of long-term memory formation, which is supported by the hippocampus and surrounding limbic cortical brain regions.
By design, IBT researchers are focusing on the development of the underlying science and engineering required for a cognitive prosthesis, namely, the technology for bidirectional communication with the brain, advanced modeling methods to uncover spatiotemporal coding schemes used by the brain to represent long-term memories, next-generation VLSI “systems-on-a-chip” designs for hardware implementation of the prosthesis, and finally, several paradigms that would provide appropriate vehicles for testing and demonstrating the fundamental principles of a cognitive prosthesis.
In particular great strides have been made in developing a synthetic neurosensory interface which will help restore the cortical brain region (hippocampus) and limbic cortical system that has been damaged/diseased.
The essential elements of such a hippocampal prosthesis include: (i) a biologically-based mathematical model that mimics the function of hippocampal neurons, (ii) hardware implementation of the model to achieve miniaturization, parallel processing, and rapid computational speed, and (iii) penetrating electrode arrays to transmit inputs to the hardware device from brain regions normally afferent to the damaged region, and to transmit outputs from the hardware device to brain regions normally efferent to the damaged cortical neurons. Thus far, prototype neural prosthetic systems have shown that memory loss can be restored in vivo that have had damage to the hippocampus region.
NEURAL SCAFFOLDS
Synethetic Cellular Scaffolds for Stem Cell Treatment for AMD
Mark Humayun, MD, PhD and David Hinton, MD, were awarded a $38 million grant from the California Institute for Regenerative Medicine (CIRM) to develop a stem cell therapy for age-related macular degeneration (AMD). Through a cross-disciplinary approach, both Principal Investigators assembled a team of world experts comprised of four major schools and institutions: University of Southern California Eye Institute (USC Roski Eye Institute), University of California-Santa Barbara, California Institute of Technology and City of Hope.
AMD is the nation’s leading cause of blindness in the elderly, with over 2 million who have gone blind and over 250,000 who are going blind each year. AMD affects central vision where individuals are unable to focus straight ahead or even drive.The disease is characterized by a loss of retinal pigment epithelial (RPE) cells, which are located in the back of the eye known as the retina. The loss of RPE are localized to a central region of the retina known as the macula. A novel stem cell-based treatment, CPCB-RPE1, has been developed for patients with dry age-related macular degeneration (AMD), particularly those with geographic atrophy (GA), the advanced form of dry AMD. In the normal retina, the light sensing part of the eye, the photoreceptor cells responsible for vision are supported metabolically and structurally by retinal pigmented epithelial (RPE) cells. Geographic atrophy is characterized by dysfunction and loss of RPE cells, followed by photoreceptor loss. Loss of RPE cells is believed to be a critical contributor to photoreceptor loss and decay of vision.
This novel stem cell treatment merges medicine and engineering, taking regenerated RPE and seeding them onto a synthetic membrane, which could then be placed underneath the diseased portion of the retina. The implanted scaffold of RPE are localized and can function to support and replenish photoreceptors of the retina, which would help restore and prevent vision loss in patients with AMD. Figure A and B below, show the stem cell derived RPE and bioengineered scaffold, respectively. Preclinical and human studies support the premise that replacing dead or dying RPE cells in dry AMD could be a way to slow the disease process, slow vision loss and even improve vision. CPCB-RPE1 treatment is composed of human embryonic stem cell (hESC) derived RPE cells that are seeded onto an ultrathin parylene membrane with diffusion properties similar to that of the native Bruch’s membrane of the retina. Similar to a native eye, the implant provides a single monolayer of RPE cells on a permeable membrane support to restore nutrient and support functions provided by RPE that have deteriorated in patients with advanced AMD.
The implant is delivered underneath the retina facilitated by a custom delivery tool. Preclinical safety and efficacy studies have shown that CPCB-RPE1 survives in the subretinal space, promotes photoreceptor survival, and improves visual behavior in preclincal models. This unique stem cell therapy was implanted in vivo by Biju Thomas, PhD, assistant professor of research in ophthalmology. Safety and efficacy of the implant was confirmed based on the preclinical studies. As well, results indicated that the stem cell therapy successfully decreased the progression of retinal degeneration in rats. In head-to-head preclinical studies, the CPCB-RPE1 implants showed superiority to single cell RPE suspensions in cell survival, biological function and improvements in visual acuity. Together, these data provide valuable proof-of-concept data to support the development of CPCB-RPE1 for geographic atrophy, a condition that today has poor prognosis, tremendous quality of life impact, and no available treatment options. In this ongoing phase I/IIa clinical trial we are assessing the feasibility of delivery and safety of CPCB-RPE1.
These findings are under evaluation by the FDA in a Phase I/IIa clinical trial in humans. The RPE seeded membranes are manufactured by City of Hope for the clinical trial. The Phase 1 clinical trial, led by Dr. Amir Kashani has begun. The study will include two cohorts of patients. For the first cohort, the study population will be patients with advanced, dry AMD with evidence of significant geographic atrophy. As the safety and tolerability of CPCB-RPE1 is demonstrated in the first cohort, patients with less advanced disease will be recruited into a second cohort in this Phase I/IIa clinical trial and assessed accordingly.
Novel Bio-scaffold for trauma
Beyond addressing neursensory disorders, IBT is also developing biomaterials-based solutions to prevent neurosensory degradation in the eye caused by trauma. Penetrating injuries to the eye can lead to retinal detachment and blindness if left untreated for days. IBT is currently collaborating with industry and U.S. Army to develop different “patch” technologies to temporarily seal penetrations of the cornea or sclera. These biomaterials may give patients time to see a specialist without risk of vision loss (Jack Whalen, PhD).
NEUROPHOTONICS
Neurophotonic Prosthetic Systems
The aim of the neurophotonics platform is to develop novel neurophotonic prosthetic systems/devices in which a key component is a nanoscale photoswitch (or a photovoltaic nanoswitches, PVN) that makes neurons that are not responsive to light respond to light. A neuron is a cell that is activated by electrical stimulation and is capable of transmitting information through electrical and chemical signals. In our approach, the neurons will be treated with novel nanoscale photoswitches having customizable photophysical (light yielding) properties, which will facilitate light modulation of neuronal electrical activity. The creation of neurophotonic systems that act as nano-photoswitches, or tiny devices implanted in the eye, can effectively by-pass the diseased cells and induce normally non-photosensitive neurons to be able to respond to light. The novel photoswitches have the potential to significantly expand the power of neuroprosthetics.
Retinal Cellular Prosthesis
Restoration of visual response in patients blinded by retinal degenerative diseases has been clinically challenging. Despite a progressive and severe loss of photoreceptors, the inner retinal neurons sending visual information to the visual cortex are relatively spared, providing a target for therapeutic intervention. Electrical stimulation of the inner retinal neurons has been shown to elicit visual perception in blind patients. More recently, optogenetic and biochemical tools have been developed to engineer light sensitivity in cells, and preclinical studies showed promise in restoring vision. In collaboration with Dr. Robert Chow’s lab, we aim to develop a new way to use light to control neural activity by novel photovoltaic nanoswitches (PVNs). PVNs are embedded in the plasma membrane and illumination generates an electrical dipole that charges the cell membrane and reversibly alters neuronal activity. They eliminate the need for invasive surgery and expression of foreign proteins, and they function at visible wavelengths and ambient light intensities. To impart light-sensitivity to retinal ganglion cells (RGC) of a diseased eye that have lost it’s photoreceptors, a periodic intravitreal injection of photoswitches designed to target the RGC cell membrane would be all that is needed. RGCs are vital to visual function as they are cells that transmit images from the retina to the brain from information captured by photoreceptors. Essentially the proposed neurophotonic prosthetic is a hybrid of an electronic component and an external intraocular camera (IOC), that serves as a neural interface, sending electrical signals back to the eye where neurons injected with photoswitches are selectively activated. At the front end, an extraocular or intraocular camera (IOC) with camera chip and back-projection system serves to process images, modulate the image (in terms of wavelength, intensity, frequency, and duty cycle), and project the image onto retinal ganglion cells (RGCs), previously treated by intravitreal injection of PVNs. The IOC in this figure is enlarged relative the eye for illustrative purposes.
We have successfully showed that the PVN, synthesized in Dr. Harry Gray’s lab from CalTech, confers light sensitivity in dissociated cell cultures. We recently demonstrated that in photoreceptor-degenerate rats, whole-mount retina treated with PVN showed illumination-induced increase in spike frequency in the retinal ganglion cells. Furthermore, intravitreal injection of PVN in vivo restores light-induced electrical activity in the superior colliculus and pupillary reflex in the blind rats. This study lays the foundation for developing a new generation of artificial retina as an alternative, novel treatment for the visually impaired patients.
Photoactivatable Nano-Cage Compounds
Our researchers are currently designing a new class of optically activated compounds for neuromodulation. These “caged” compounds may be released once activated by light. The new compounds are inactive or “caged” until they are activated by illumination by infrared light. Infrared light is able to penetrate more deeply into tissues than visible light. The novel caged compounds will augment the power of prosthetic devices, enabling use of different wavelengths of light to activate different processes. We have begun work on molecular targeting of the photoswitches to specific ion channels on specific neurons, taking advantage of the high-affinity binding of ion channel-active peptides (iCAPs) to specific ion channels on retinal ganglion cells. In addition, we have begun conceptual development of the image processing and projection hardware for the front end of a retinal cellular prosthesis system, which may be used to restore vision to patients who are blind due to retinitis pigmentosa or age-related macular degeneration.
NEURORX
Neurosensory disorders of the brain and eye affect a growing number of people. The etiology of these disorders spans a spectrum of factors, which include aging, genetic predisposition, exposure to harmful materials, unhealthy diet, physical injuries and underlying diseases. Physical injuries such as blunt force trauma can activate acute inflammatory responses that can lead to chronic inflammation. This highlights the need for effective therapies for many of these important diseases. Despite this urgent need for treatment of these types of diseases, the lack of effective therapy continues to be one of the greatest health challenges of our time.
A key goal of the Institute for Biomedical Therapeutics (IBT) is to pursue and exploit innovative new approaches to develop breakthrough therapy. By bringing together an integrated team of expert scientists, engineers, and biomedical researchers, the IBT is in a unique position to develop innovative solutions integrating the state of the art technologies in molecular therapeutics, pharmaceutical delivery, biomaterials, nanomedicine, and medical devices into a seamless paradigm-changing care for patients.
Towards this goal, the IBT has formed the NeuroRx team. This team will focus on the design and development of breakthrough therapies based on key molecular and pharmaceutical insights for each disease. The NeuroRx team will also establish effective means for their delivery to targeted sites by using suitable formulation, bioengineering techniques, and nanotechnology. Enabled by the multidisciplinary and closely collaborative team of IBT, these integrated systems will enhance selectivity and specificity to improve efficacy, while reducing the potential for adverse effects. The result of this strategy is a significantly enhanced overall outcome for the treatment of neurosensory ailments, while ensuring the safety and well being of the patient.
NeuroRX focuses on implementation of novel drug delivery systems and bioelectronic implants that may deliver drugs across the blood-brain barrier in a highly selective manner. Novel micro and nanoeletromechanical systems known as MEMs or NEMs have been developed to deliver established and novel drug platforms. The technology has been applied to MEMS based drug delivery systems. This innovative bioengineering invention along with other potential drug delivery systems will revolutionize the field of neuropharmaceuticals.
In developing new systems for “smart” drug delivery, NeuroRx utilize the substantial expertise and experience of our faculty members to develop systems that can be useful in a wide range of ocular diseases. Using principles of microelectromechanical systems (MEMS) engineering, we have designed and tested prototypes of a small, refillable, implantable ocular drug pump (mini-drug pump) on the benchtop and in preclinical testing. Over the next few years, long-term biocompatibility testing will be conducted with various pharmacological agents to determine the device’s ultimate potential for ocular drug delivery. However, given preclinical results, prospects appear excellent for treatment of currently refractory problems encountered in conditions such as dry and wet aged related macular degeneration (AMD), uveitis, glaucoma, traumatic brain injury and neurodegenerative diseases (neurosensory disorders).
Ongoing Projects
The NeuroRx team in engaged in a wide range of novel therapeutics for the treatment of neurosensory disorders. They have employed novel strategies to significantly advance the efficacy of the patients.
Brain Project as applied to Neurosensory Disorders
Diseases that affect the brain such as stroke and trauma remain major causes of morbidity and mortality. Traumatic brain injury (TBI) alone occurs in more than 1.5 million Americans each year. In addition to being life threatening, many milder forms of TBI’s can lead to serious long-term cognitive and physical sequelae. NeuroRx is developing a paradigm changing nanocage-infrared-triggered (NIT) therapeutic system for use during the initial period or “golden hour(s)” after sustaining a TBI. The science used to engineer the NIT system will make it ergonomic and robust enabling first responders to use this system to limit insults initiated by TBI.
The NeuroRx is developing a first-of-its kind preventative treatment system for TBI. The uniqueness of the NeuroRx approach is seamless integration of the advanced principles of nanotechnology, chemical biology, and neurophotonics into a minimally invasive therapeutics that can be used by first-responders at the site of the accident to treat and mitigate the damage from the TBI in the initial period after the injury “golden hour(s)”. Specifically, the NIT system enables an intravenous (IV) administered nanocage-drug complex to be uncaged only at the site of injury. The nanocage-drug complex gets across the damaged blood-retinal and blood-brain barrier into the area of brain injury and then is released by infrared light transmitted across the intact skull by a wearable time-gated LED emitter array contoured much like a swimmer’s cap to fit the skull (Figure above). The time-gated feature results in not releasing the nanocage-drug while traversing in blood vessels but only when is it sequestered in the injured brain area. Hence, this system is engineered such that it can treat, in a highly directed/localized manner, the site(s) of injury without the a priori need for CT or MRI imaging to identify the location of the injury.
Bioactive Lipids
In conjunction with developing drug delivery devices, NeuroRx is also designing new drug therapies for treatment of ocular diseases like wet AMD, which is a leading cause of blindness in western countries. Approximately 15 million individuals in the U.S. suffer from some form of AMD, where the prevalence is expected to double by 2020. AMD is classified as either atrophic (dry) or exudative (wet) AMD; dry AMD is characterized by progressive degeneration of RPE and photoreceptors, while wet AMD has abnormal new vessel formation (i.e., choroidal neovascularization (CNV)), which bleeds into the retina damaging the retina (see Figure 1). It is estimated that 1.6 million people have the progressive form of AMD where active blood vessel growth and/or blood vessel leakage is part of the clinical presentation.
Current treatments for wet AMD primarily focus on inhibiting a protein called vascular endothelial growth factor (VEGF) that promotes the formation of new and leaky blood vessels. The most commonly used therapeutics include the biologic drugs LucentisTM, AvastinTM and EyleaTM, which must be administered via injections directly into the eyes every one or two months. Although these drugs are designed to bind to VEGF and limit its actions, they do not eliminate the source that produces VEGF. Additionally this type of therapy can be associated with a variety of side effects including stroke. Although these interventions are effective in addressing retinal edema and formation of new blood vessels, they have drawbacks due to the invasive intravitreal injections required on a regular basis. Moreover, the effectiveness of these therapies is limited to only one-third of AMD patients. This represents a major unmet therapeutic needs to develop new and more effective small molecule drugs that can better address the causes of this disease.
NeuroRx initiatives have focused on the deployment of novel anti-inflammatory agents for the treatment of several major diseases of the eye. This technology was based on the work of NeuroRx members, which provided insights into inflammation and mechanisms leading to tissue resolution. This insight has propelled the NeuroRx team to develop compounds that promote tissue restoration from damaged and inflamed state back to homeostasis. Compounds of this type can also inhibit the formation of new blood vessels, or angiogenesis, which is the source of a number of ophthalmic disorders such as AMD.
Mas Agonist
The renin angiotensin system (RAS) is most known for its ability to regulate blood pressure through the action of the first identified active peptide, angiotensin II. However it was discovered that other peptides of the RAS could accelerate wound healing and have regenerative properties. It was discovered that angiotensin (1-7) (A(1-7)), a metabolite of angiotensin II, is able to accelerate the regeneration of injured tissues, including bone marrow and skin. Members of the NeuroRx are leaders in exploring how to harness the protective arm of the RAS for the treatment of neurosensory, metabolic and ocular diseases. To this end, NeuroRx is developing novel formulations and delivery methods to enhance the patient adherence, which include nanoparticle and MEMs technology.