|Photoreceptor preservation after IV injection of MSCs.|
The primary goal of the Wang laboratory is to restore vision in degenerative retinal diseases using cell-based therapy.
Degeneration of photoreceptors as a result of genetic defects affecting either the photoreceptors themselves or associated cells such as the retinal pigment epithelium represents the leading cause of blindness in humans for which no suitable treatment exists. The advance in stem cell biology offers great potential to treat retinal degeneration that affects millions of people worldwide. Indeed, our preclinical studies on animal models have led to three human clinical trials using stem cells to treat age-related macular degeneration.
Development of noninvasive cell-based therapy for retinal degeneration and associated vascular pathology
Retinal degeneration and related diseases are the leading cause of blindness and represent a major public health burden with economic and social impacts. As photoreceptors are lost, the development of secondary vascular pathology causes disastrous consequences for vision. There is no effective treatment available. Our most recent study revealed that a single intravenous injection of bone marrow-derived mesenchymal stem cells (MSCs) at early stages of degeneration can preserve photoreceptors, sustain visual function, and limit pathological vascular changes in a rodent model of retinal degeneration. We propose to develop a treatment protocol that preserves vision and limits vascular pathology using noninvasive stem cell therapy in rodent models for retinal degeneration.We hypothesize that systemic administration of MSCs to treat ongoing retinal degeneration will slow the progress of photoreceptor loss and stabilize/repair the secondary vascular pathology by promoting the release of paracrine and autocrine mediators.
|Retinal blood vessels by IV injection of FITC-dextran.|
The following specific aims are proposed:
1. Determine dose-response and long-term safety and efficacy of MSC treatment at early stages of degeneration in the RCS rat.
2. Investigate the neuro-vascular protective effects of MSCs at later stages of degeneration in the RCS rat and in Elovl4 mouse.
3. Examine the molecular mechanism of MSC homing to the retina and efficacy after intravenous administration. If we obtain positive results in animal models, the current extensive clinical experience using MSCs as therapy for both regenerative and degenerative medicine, means this treatment could have a realistic likelihood of translation to the clinic.
Cell-based therapy for traumatic optic neuropathy
Traumatic optic neuropathy (TON) can lead to irreversible blindness and represents a major public health burden with both economic and social impacts. TON results from trauma to the optic nerve from head and eye injuries in both military and civilian populations, such as blast-related combat trauma and accidents. There is no effective treatment as yet. Advances in stem cell biology hold great promise for treating a broad array of neurological disorders. Until now, however, the effectiveness of stem cell therapy in TON has been limited; the current method of direct intravitreal injection can cause donor cells to cover the back of the lens and block the passage of light into the eye. In addition, TON affects both the optic nerve and its target neurons in the visual system, which provides vital retrograde trophic support to the optic nerve. Therefore, a rational treatment strategy that targets both local and the related target neurons in the visual system is urgently needed.
CTB labeled optic nerves with
Combined local and global cellular therapies to treat retinal degeneration
Degenerative retinal diseases affect over 10 million individuals in the United States alone. Crucially, current treatment is still very limited. Work from collective laboratories suggests that a stem cell-based approach to the rescue of retinal cells may be effective in neurodegenerative diseases. We have shown that human cortex-derived progenitors (hNPCctx)offered near normal preservation of photoreceptors and visual function when injected subretinally into a rodent model for retinal degeneration. However, subretinal injection protects only a small part of the retinal area, leaving the majority of the retina to undergo progressive degeneration, including vascular leakage. The vascular leakage dramatically compromises the beneficial effects to the retina. A better strategy that targets both local and global degeneration is needed to treat retinal degeneration. Our previous study demonstrated that systemically injected adult bone marrow-derived mesenchymal stem cells (MSCs) offer global preservation of photoreceptors and limit the secondary vascular leakage. Here we investigate whether combined local and global cell therapies would enhance the efficacy in preserving vision.
Functional evaluation of vision
Functional evaluation, correlated with morphology, is the key to examining whether an intervention is effective in preserving vision.
|Optokinetic response (OKR): Aquick, non-invasiveway to test an animal’s visual acuity.|
|Full field electroretinograpy (ERG): Examines overall retinal responses to light stimulation. It is not sensitive enough to measure the effect of a local treatment.|
|Luminance threshold recordings from the superior colliculus (SC): Measures retinal sensitivity to light point-by-point, based on the topographic projections of retinal ganglion cells to SC. It is a great way to measure the effects of local and global treatments.|