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Stem Cells for Neuroprotection of Photoreceptors in Retinitis Pigmentosa

Funding Type: 
Disease Team Research I
Grant Number: 
Funds requested: 
$4 327 722
Funding Recommendations: 
Not recommended
Grant approved: 
Public Abstract: 
The targeted disease is retinitis pigmentosa (RP), is a severe form of blindness that runs in families. This disease is not common, yet represents an attainable near term target for stem cell therapy for a number of reasons: 1) RP destroys the light detecting cells of the retina but generally leaves the rest of the visual system and body unharmed, so the clinical goal is circumscribed; 2) RP is prototypical of degenerations of the nervous system, so a cure for this less common disease would accelerate progress towards new therapies for a range of more familiar conditions; 3) scientific research has shown that the rods and cones can be spared in animals by transplanting particular types of stem cells, so the scientific feasibility of treating RP has already been established in principle. The therapeutic approach is to save the light sensing cells of the eye (rod and cone photoreceptors) in people going blind using a type of stem cell obtained from the immature retina, but not from early embryos. These particular stem cells from the retina, known as progenitor cells, are capable of rescuing photoreceptors from degeneration following transplantation to the eye. These same cells are also highly efficient at turning into rod photoreceptors and this provides another more sustained pathway by which they preserve the crucial cone photoreceptors. In addition, there is evidence that the stem cells themselves might become functional photoreceptors and thereby stabilize the retina by directly replacing the dying cells in the patient’s eye. Thus, transplanted stem cells could treat the targeted disease of RP in multiple ways simultaneously. Importantly, there are a host of reasons why clinical trials in the eye are easier and safer than most locations in the body. The eye is an important proving ground for stem cell-based therapies and provides a stepping stone to many incurable diseases of the brain and spinal cord.
Statement of Benefit to California: 
Benefits to the state of California and its citizens are both direct and indirect. The direct benefit is medical in that there is currently no cure or established treatment for the individuals and families that suffer from the dreadful hereditary blindness known as retinitis pigmentosa. In addition, there are many people in California and throughout the world that suffer from degenerative diseases of the retina and central nervous system that could benefit from the type of stem cell therapy proposed in the current application. The rapid progress that could be achieved via this proposal would help legitimize the use of stem cells and should thereby accelerate the development of stem cell-based therapeutics for a wide range of other diseases. In so doing there would be an indirect benefit to California by making our state a focal point for stem cell breakthroughs. This would increase medical capabilities, strengthen the {REDACTED}, and energize local biotechnology companies with outside investment and a payoff in jobs and tax revenues.
Review Summary: 
This application proposes the development of a novel treatment for retinitis pigmentosa (RP), an incurable genetic disease characterized by degeneration of photoreceptors in the eye. RP has an onset that transpires earlier and with symptoms more severe than age-related macular degeneration, and it culminates in complete blindness. The proposed therapy involves transplantation of allogeneic retinal progenitor cells (RPCs) into the subretinal space of RP patients. The applicant proposes to utilize the neuroprotective capacity of RPCs transplanted into the eye to rescue photoreceptors from degeneration. These RPCs are also highly efficient at differentiating into rod photoreceptors, and this property may provide another more sustained pathway by which they can preserve the crucial cone photoreceptors. In addition, the transplanted stem cells themselves might become functional photoreceptors and thereby stabilize the retina by directly replacing the dying cells in the patient’s eye. To advance the proposed treatment, the applicant describes establishing the manufacturing process with human RPCs and developing a preclinical in vivo model to facilitate proof-of-concept studies. Preclinical safety and efficacy studies will be followed by cGMP scale up and production and a planned pre-IND meeting with the FDA. If successful, the applicant plans completing GLP safety/efficacy studies in preclinical models using GMP human RPCs and preparing the IND filing. Reviewers were supportive of the proposal’s focus on RP and believed that the project addresses a significant, unmet medical need. They were also supportive of the scientific rationale and overall approach. In particular, they found the use of RPCs neuroprotective ability to be a compelling therapeutic strategy, because it has the potential to both stabilize existing diseased areas and provides an opportunity for retinal regeneration through the differentiation of RPCs into newly functional rods. Neuroprotection via neural progenitor cells, like RPCs, to rescue host neurons and retinal pigment epithelium is a promising approach that is supported by preclinical data. Furthermore, reviewers noted the simplicity of the therapeutic approach as the cell suspensions can be delivered into the subretinal space through a basic surgical procedure under local anesthesia. The possibly immune privileged nature of the retina adds to its attractiveness as a cell therapy site. Reviewer enthusiasm for the proposal was severely dampened, however, by concerns about the project’s stage of maturity andlikeliness to achieve an IND filing in the time proposed. Reviewers noted the applicant’s data showing the feasibility of expanding human RPCs, transplanting them, and improving retinal health. In addition, the availability of preclinical models that accurately reproduce RP pathology was found to be a key strength of the proposal. However, reviewers thought the application did not include sufficient preliminary work, and important details demonstrating feasibility of scale-up for cell production were missing. A particular concern was that a homogeneous therapeutic cell line has not yet been successfully derived. Necessary standard operating procedures for cell production, procedures for reagent verification needed for the GMP-level preclinical studies, and overall workforce on the team were viewed as inadequate. Furthermore, there were concerns about the lack of detailed plans for quantitatively measuring the survival and functionality of engrafted cells. In light of these serious deficiencies, the review panel suggested that this application might be more appropriate as a submission for an Early Translational Research RFA. The review panel also expressed reservations about inadequate details regarding how the research will move to GMP-level cell production. For example, basic questions concerning the duration of preclinical safety studies or how a GMP manufacturing facility would be used were not addressed. Although the applicant indentified preclinical safety studies assessing biodistriubtion and tumorigenecity as critical for an IND, a general toxicology study to consider non-specific adverse effects was omitted from the plan. Adequate details about how cells would be handled and preserved after manufacturing were not provided. The applicant did not describe appropriate endpoints for a Phase I clinical trial, and other key developmental issues, such as standards for the biological potency of human RPCs and properties of the optimal delivery vehicle, were left unresolved. Reviewers had concerns about the applicant’s proposed milestones and timeline. Although some reviewers felt the milestones were appropriate and achievable, others considered some key milestones and “Go / No Go” criteria as incompletely developed. Furthermore, the timeline was judged to be overly ambitious and unlikely to be achievable, given the proposed personnel and project expertise. Reviewers doubted that the project goals could be accomplished within the proposed time span. The project team’s composition was a key focus of the reviewers’ concerns. The applicant is an accomplished investigator and has published extensively on RPCs and retinal regeneration. However, the assembled personnel do not represent a true multidisciplinary team. Specifically, the team is essentially composed of the PI and his/her research group, with some work subcontracted out to a series of consultants. Reviewers were concerned by the lack of clear definition given of the consultants’ roles, and it was unclear that personnel with appropriate expertise would be adequately committed to the project. Additionally, a full time project manager to supervise the information flow and coordinate the various aspects of the project was not included. Reviewers thought the equipment costs were justified but considered the cell culture costs to be severely underestimated. In addition, there were concerns about the lack of budgeting for a GMP expert(s) to help complete the Chemistry, Manufacturing and Controls (CMC) section of the IND; reviewers considered the CMC to be a substantial undertaking and were concerned with the lack of a plan or needed expertise to address this critical component of the IND. The research environment and institutional letters of support were considered adequate. The applicant proposes to deliver allogeneic RPCs to the subretinal space of the patients diagnosed with RP, an incurable and hereditary blinding disease. Strengths of the proposal included the focus on an appropriate disease target and the scientific rationale underlying the project. Critical weaknesses included the poor feasibility of the research and development plan, lack of adequate attention to GMP issues, absence of a therapeutic cell line, and a deficient multidisciplinary research and development team.
  • Joy Cavagnaro

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