Early Translational IV
$5 282 342
Our proposal is unique in that having characterized how stem cells influence their environment by talking to each other and to other cell types, we can now successfully harvest their communication signals, called microvesicles, and may safely and effectively treat retinal diseases with them. The leading causes of new blindness in the developed world are retinal diseases. We will not be transplanting stem cells, but harvesting their regenerative signal and treating afflicted eyes with the signal alone. We will focus on retinitis pigmentosa, cone- and cone-rod dystrophies but our novel regenerative strategy could potentially be used to treat patients across the entire spectrum of blinding diseases, including retinopathy of prematurity and Stargardt disease in children, diabetic retinopathy and myopic macular degeneration in adults, and AMD and glaucoma in seniors. By reversing disease-based retinal damage we will reduce suffering and vision loss. Hypothetically this treatment may be much safer than stem cell transplantation given the decreased risk of immune rejection or tumor formation. We will study human stem cell-derived microvesicles effects on a mouse model of acute retinal injury and determine the % recovery of damaged cells and functional retina. We will then assess the treatment in the rd1 mouse, a model of retinitis pigmentosa that rapidly loses all photoreceptors, to confirm the microvesicles’ capacity for regeneration of most retinal degenerations.
Statement of Benefit to California:
Retinal diseases are the leading causes of new blindness in Californians. This proposal introduces a novel, regenerative treatment strategy with the potential to safely and effectively treat patients with retinal diseases. Specific examples of prevalent retinal disease include retinopathy of prematurity, Stargardt & retinitis pigmentosa in the pediatric age, diabetic retinopathy & myopic macular degeneration in working age Californians, and AMD & glaucoma in senior Californians. A number of orphan retinal diseases are also potential targets. A therapeutic approach that could treat and even reverse disease-based retinal damage would provide an almost unimaginable reduction in suffering. In addition, the ongoing care and extensive adaptive measures necessitated by the current lack of successful therapeutic modalities are an enormous burden on the pocketbooks of both the State and affected individuals. Recovery of the damaged retina would offer tremendous functional and fiscal benefits to California and its residents. Further, the innovative approaches described in the project herein would benefit California because they could have application not only for the treatment of diseased eyes but also for other diseases. When this project enters the clinical phase it will likely attract new biotechnology investment in California and funding by the federal government. This proposal well represents the broad mission of CIRM and the objective of the Early Translational IV Awards program.
The objective of this Development Candidate award (DC) proposal is to develop intraocular injectable stem cell-derived microvesicles (SMV), for the treatment of retinal degenerative diseases. SMV are released into the media by the cells and are believed to be important for intercellular communication. The applicant proposes to generate and characterize hSMVs from each of several human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) lines, test delivery, dose, and preliminary safety and study the effects of hSMVs on the recovery of damaged cells and functional retina in in vivo models of acute retinal injury and retinitis pigmentosa. Objective and Milestones - The Target Product Profile is well laid out and clear. - While overall the milestones are reasonable, subsequent milestones are all dependent on the success of Milestone 1 since a candidate therapeutic is dependent on the generation and activity of human stem cell-derived microvesicles. Rationale and Significance - The investigators present a logical rationale based on their findings with mouse stem cell derived microvesicles. - There is currently no reliable treatment for inherited retinal degeneration; therefore a successful therapy could have major significance for regenerative medicine in the eye. Feasibility and Design - The proposal lacks any preliminary data with human pluripotent stem cell-derived microvesicles. - The preliminary data support the notion that mouse derived microvesicles can have regenerative effects on retinal cells, however, while reviewers found the data intriguing, they noted that the effects were small and not compelling. - The feasibility of achieving the goals of a DC project within three years was viewed as low. - While the animal models are well described and appear relevant for the proposed studies, sub-retinal injection could lead to a retinal detachment requiring recovery time that may justify longer duration animal studies than those proposed. - Since injection of stem cell-derived microvesicles may lead to inflammation, immunosuppression or using immunodeficient mice should be considered. Qualification of the PI and Research Team - The PI, Co-PI and team are well published and have the expertise to conduct the proposed studies. - Some reviewers found the budget reasonable; others considered it excessive with respect to personnel and equipment. Collaborations, Assets, Resources and Environment - The investigators have sufficient lab facilities, access to cores and a great academic environment with translational research and support facilities. Responsive to the RFA - Activities described are well within the scope of the RFA, as stem cells are used to generate the microvesicles. - Although the approach is novel and intriguing, there are other active projects in CIRM’s portfolio targeting ocular diseases.