The targeted disease is retinitis pigmentosa (RP), a severe form of blindness that often runs in families, but other times arises spontaneously from genetic errors. This disease is not overly 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 in the back of the eye, yet 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 degenerating rods and cones can be saved in animals by transplanting particular types of stem cells, thus the scientific feasibility of treating RP in this way has already been established in principle.
The therapeutic approach to be championed here 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 saving photoreceptors from degeneration following transplantation to the eye. These same cells are also highly efficient at producing new 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 otherwise incurable diseases of the brain and spinal cord.
As part of the current project, our cell type of interest will be grow under conditions ensuring pharmaceutical standards are met. The resulting cells will be tested in animals for safety and to make certain that they are therapeutically potent. An application will be made to the FDA seeking approval for the use of these cells in early clinical trials. Following approval, a small number of patients with severe RP will be injected with cells in their worse-seeing eye and followed clinically for a specified period of time to determine the safety and effectiveness of the treatment.
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, such as age-related macular degeneration (AMD), and the central nervous system that could benefit from further development and alternate applications of the type of stem cell therapy proposed in the current application. The rapid progress into the clinic that could be achieved via this proposal would help legitimize the use of stem cells for previously incurable diseases and should thereby accelerate the development of stem cell-based therapeutics for a wide range of other conditions. 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 state’s educational system, and energize local biotechnology companies with outside investment and a payoff in jobs and tax revenues. In the current economic situation, the citizens of the state are looking for a return on their investment in stem cell research. The leadership for the state is looking for a novel technology to reinvigorate the economy, provide desirable jobs, and reaffirm the flagship image of California. The project presented in this application has a real chance of provide that sort of spark.
The goal of this proposal is to advance allogeneic human retinal progenitor cells (RPCs) as a therapy for retinitis pigmentosa (RP), a rare but severe form of hereditary blindness that progressively destroys the photoreceptor cells in the retina which are necessary for receiving and transmitting visual information. The applicant hypothesizes that transplanted RPE could, by differentiating, regenerate lost photoreceptors. The applicant proposes to manufacture RPCs and conduct preclinical safety studies to enable the filing of an IND, and will also conduct clinical trials in patients with RP. A two-tiered clinical trial strategy is proposed comprising an initial clinical trial using cells made according to Food and Drug Administration (FDA) good tissue practice (GTP) regulations, followed by a second study conducted using cells manufactured according to good manufacturing practice (GMP) regulations. Patients with RP will receive RPCs in the most-affected eye and will be followed clinically for a specified period of time to determine the safety and effectiveness of the treatment.
Significance and Impact
- There is an unmet need for the treatment of RP and this work, if successful, is likely to be of high impact.
- The preliminary data presented indicate that this approach has promise and
suggest that RPCs may present an important therapeutic intervention in RP.
- Based on the data provided it is difficult to draw a clear conclusion as to how this is superior to other approaches using cell transplants.
- The proposed method and site of delivery of RPCs is surgically simple and relatively safe from the standpoint of risks such as anesthesia and infection, although there are other serious risks with this approach such as a greater likelihood of an immune response.
- The applicant has presented compelling non-clinical data in multiple species. Three human clinical case reports performed outside the USA are consistent with the non-clinical data.
- It was clear that RPC-mediated photoreceptor rescue (rather than regeneration) was the predominant effect; no guidelines are provided as to how long they expect this (the effect) to last.
- The scientific rationale is clear and strong.
- The 2-tier clinical strategy proposed is not rational.
Therapeutic Development Readiness
- The applicant proposes to use "GTP" RPCs initially and then switch to "GMP" RPCs; the FDA may consider them to be two different products. A single therapeutic candidate should therefore be chosen (GTP vs GMP).
- It seems they have not selected their lead candidate yet as required by the RFA, so there is a question of readiness.
- The cells aren't optimized, which calls into question the feasibility of the timeline.
-They need to first understand the cells and finish the optimization before doing any other safety studies.
Feasibility of the Project Plan
-The proposed 2-tier clinical plan to use GTP RPCs initially and then transition to GMP cells was a major issue in the review:
- There is concern about the identity of the GTP versus GMP cells; the products may not be the same; the GTP to GMP transition is a concern; results may be difficult to translate from one study to the other.
- More clarity is needed to understand what is different between GTP and GMP RPCs and whether or not clinical data from GTP RPCs is predictive of GMP RPCs. A major risk of this project is that the cells from the GTP process will have different biological properties from the GMP cell product.
- No data are available to support the comparability of the GTP and GMP cells; the FDA may very well consider them two different products.
-Reviewers expressed concern about the lack of immunosuppression in the proposed clinical trial. The applicant has not provided enough evidence that there is lack of graft rejection; graft rejection can occur in the eye without evidence of inflammation, so the claim of no rejection is unsubstantiated. Immune rejection may be an issue, especially in the event of re-treating.
- Focusing only on the GMP RPC, the development plan outlined by the applicant appears comprehensive and entails a number of manufacturing activities and a series of non-clinical studies that are typically necessary for a long term persisting cellular therapy product.
- It does not seem the applicant intends to perform safety studies with the GTP RPC, but only for GMP RPC. It is unclear why the applicant believes the safety studies required for GMP RPCs will not be needed for GTP RPCs.
-Adventitious virus testing will be performed on the master cell bank only if requested by FDA. The responsible action would be to perform this testing regardless of FDA input.
- The applicant will need to do tumorigenicity studies, but the proposed timeline does not reflect this.
- Clinical trial monitoring procedures are not described.
- The applicant proposes to identify candidate potency markers using a proteomics approach. Reviewers were concerned that this sounds like a very large project in itself and may not be completed during the grant funding period.
Principal Investigator (PI) and Development Team
- The PI and development team are excellent and a strength of the proposal
-The GMP manufacturing facility appears to be qualified.
- The clinical investigators are excellent as are the clinical sites.
-The entity responsible for clinical trial monitoring is not described.
Collaborations, Resources and Environment
- Resources and environment: Outstanding
Budget (Assessment of the budget was conducted separately from the overall scientific evaluation and points or concerns raised in this section did not contribute to the scientific score. This section highlights items that must be addressed should the application be approved for funding. )
- There is significant budgetary discrepancy between the two clinical sites that is not justified adequately.
- The budget for the toxicology subcontract is not justified adequately;
- The project seems over-resourced.
- Russell Lonser