Public Abstract:
Vision loss due to the degeneration of the retina, the light sensitive structure in the back of the eye, and the cells that support it (retinal pigment epithelium or RPE) is a major health issue in the population over 65 years of age. Although visual disability affects a person’s quality of life in terms of independence and productivity, it also has physical, emotional, social and financial consequences not only on patients but also on their families. Combined, the wet and dry forms of age-related macular degeneration (AMD) represent the leading cause of blindness in adults over 40 years old. There is currently no cure for these diseases.
Although current available treatments aim to stabilize wet AMD by antibodies directed against vascular endothelial growth factor (VEGF), these approaches do not reverse or prevent the disease. As for patients suffering from dry AMD, only nutritional supplements have been shown to slightly reduce the progression of the disease. The potential for transplantation of various types of cells to help patients with retinal degeneration, such as AMD, is being investigated by many researchers. Some research has been focused on replacing specific cells in the retina or the RPE, while other approaches propose to use transplanted cells as a way to preserve the health of the patient’s own retinal cells, also known as photoreceptors. It is possible that such donor cells can secrete factors or substances that maintain the photoreceptors, or that the donor cells take on some of the function lacking in the patient’s retina.
Human neural stem cells are tissue-derived adult stem cells that have been shown, when transplanted into the space immediately behind the retina, to preserve vision and protect photoreceptors in an animal model of retinal disease. The results of research in animal models suggest that transplantation of these cells into patients with dry AMD may help maintain vision and slow the progress of the disease.
These human neural stem cells have undergone extensive safety testing in animal models and have also been tested in human clinical trials. The results of these trials indicate that the cell is well tolerated after transplantation into the patient and has a favorable safety profile.
The goal of this research is to conduct the first human study of neural stem cell transplantation in patients with the dry form of AMD. We anticipate that the study will enroll 10-12 patients who will receive the cells into one eye through a standard retinal operative procedure.
Statement of Benefit to California:
There is no cure for degenerative diseases of the retina. Approximately 2.2 million Californians are at substantial risk of developing retinal degenerative disorders. Age-related macular degeneration (AMD) is one of the most common retinal disorders, and it is estimated that this disease alone will affect a total of 450,000 Californians by the year 2020. The visual impairment caused by AMD not only affects the individual’s quality of life, but also places a huge burden on families and state medical resources. Current treatments are inadequate for certain types of AMD and new approaches have started to focus on the potential of cell transplantation as a means of treating disorders of retinal degeneration.
The goal of this research is to conduct an early stage trial that will test the safety and potential effectiveness of neural stem cell transplantation in patients with dry AMD. Research with animal models of retinal disease has shown that neural stem cells transplanted into the space behind the retina can protect the host photoreceptors and preserve vision. If successful, this therapy could lead to a one-time intervention that would benefit thousands of Californians by altering the progression of visual loss. California would benefit through the significant increase in the quality of life for those suffering from AMD. There would also be a reduction in health care costs associated with AMD and any future treatment would establish the state as a leader in stem cell interventions for degenerative eye disorders.
Review Summary:
EXECUTIVE SUMMARY
Project Synopsis
The objective of this proposal is to assess the safety and preliminary efficacy of neural stem cell (NSC) transplantation as a possible cell-based treatment for patients with the dry form of age-related macular degeneration (AMD). The therapeutic strategy is based on neuroprotection of remaining viable endogenous photoreceptors by the donor human NSCs. Preclinical safety studies are currently underway, and the aims of the project include submission of an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) and initiation of a Phase I/II clinical trial. It is anticipated that the study will enroll 10-12 patients who will receive the cells into one eye through a standard retinal operative procedure.
Significance and Impact
- There is no reliable treatment currently available for dry AMD, and thus, this approach targets an unmet medical need.
- Reviewers were in agreement that the proposed therapy, if successful, could have a significant impact on the standard of care and management of dry AMD.
-The basis of the proposed therapeutic approach is to provide neuroprotection of endogenous photoreceptors. However, since this approach does not address the loss of retinal pigment epithelium (RPE) that underlies AMD, reviewers were in agreement that the probability of success is low, and they had serious doubts that the approach will have a significant impact on the disease process.
- The extent of immune suppression required with this approach is not known, but this may be a significant factor in limiting success of the therapy.
Project Rationale and Feasibility
- The reviewers’ main criticism of the proposal concerned the underlying rationale for the proposed therapeutic strategy in AMD; this rationale was judged to be seriously flawed. The proposed approach focuses on neuroprotection of photoreceptors and does not address the loss of RPE. Reviewers were in agreement that since photoreceptors cannot function without an underlying RPE, a neuroprotective strategy that does not address the protection and/or replacement of damaged RPE will be unsuccessful and will not prevent the loss of vision in AMD.
- The preclinical studies provide only weak evidence to support the initiation of IND enabling studies. These preclinical studies relied on a single rodent model that is not considered a good model for AMD and whose predictive value to human disease is unknown.
-There is concern that the proposed therapy may jeopardize remaining central vision in patients because of the sheet of immature, neuronal cells that will develop in the subretinal space following such therapy.
-Although the implanted cell sheet might have the ability to elaborate trophic factors and possibly phagocytosis, these cells will not have the ability to regenerate 11-cis retinal, which is essential for photoreceptor function and the visual cycle.
-The proposed project is feasible. The applicant has already conducted a pre-IND meeting and follow up interactions with the FDA. The applicant has previous experience in conducting clinical trials and should be able to file an IND and complete a phase 1/2 study within 4 years.
- Reviewers raised significant questions about how the proposed duration and dose of immunosuppression was chosen.
- Reviewers were concerned by the absence of discussion of and plans for tumorigenicity studies.
Principal Investigator (PI) and Planning Leader (PL)
- The PI is trained as a neurosurgeon and has extensive experience working with NSCs. The PI has demonstrated successful leadership and has been the clinical and scientific leader of two successful INDs. There were some concerns regarding the lack of experience in ophthalmology. Collaboration with retinal surgeons with experience in the planned surgical technique was viewed as important.
-The PI will also act as the planning leader (PL). Since the PL has not previously worked in ophthalmology, having an adviser in that field already on board would have significantly strengthened this proposal.
