Stem cell-derived choroid plexus epithelial cells (dCPECs) as a secretory cell-of-choice for CNS therapies
Early Translational IV
$1 539 436
Can you imagine a cell that normally lives in the brain, that is born to pump, and that pumps in a way that naturally bypasses the main barrier (the blood-brain barrier) to getting drugs into the brain? If such as cell existed and one could make it, we would potentially have a way to treat not just one disease, but many, many diseases of the brain and spinal cord. With invaluable support from CIRM, we believe that we have figured out how to derive just such a cell. The goal of this proposal is to provide proof-of-concept (POC) for using these cells – which we refer to as stem cell-derived choroid plexus epithelial cells, or dCPECs – to treat brain and spinal cord diseases. In this proposal, we take advantage of an existing CIRM-funded team to target a disease that is ideal, in many ways, for this POC testing – Hurler’s syndrome, a fatal childhood disease that is caused by the absence of a single protein, which results in a slow and progressive brain degeneration that cannot be effectively treated. By engineering dCPECs to pump the missing protein at very high levels, our mission is to provide POC not only for regular dCPECs, but also for engineered dCPEC “superpumps” to treat patients with Hurler’s syndrome and a wide range of other brain and spinal cord diseases.
Statement of Benefit to California:
Our proof-of-concept proposal for therapies using stem cell-derived choroid plexus epithelial cells (dCPECs) should benefit the State of California and its citizens in a number of ways. In the short term, this project will provide employment, education and training in stem cell research for a handful of California residents, and will support California-based companies that provide supplies for the stem cell and biomedical research communities. In the longer term, success in the proof-of-concept research would provide the rationale for other dCPEC-based transplant approaches, studies and applications by academics and stem cell companies, and drug screens to identify compounds that can regulate dCPECs and allow for combined cellular-pharmacologic approaches that bypass the blood-brain barrier, a major roadblock to the development of pharmaceuticals for treating the brain and spinal cord. Such outcomes would ultimately stimulate investment in California-based companies and benefit the health of many California citizens, which could ultimately reduce the economic burden of health care in the state.
The objective of this Development Candidate Feasibility proposal is to show proof-of-concept (POC) for using stem cell-derived choroid plexus epithelial cells (dCPECs) to treat the neurodegenerative component of the fatal lysosomal storage disorder, mucopolysaccharidosis type I (MPS1, Hurler’s syndrome). This syndrome is caused by the absence of a single enzyme, which results in a slow and progressive brain degeneration that cannot be effectively treated. The goal of this project is to engineer dCPECs to over-produce the missing enzyme and to provide POC not only for regular dCPECs, but also for engineered dCPECs in a mouse model of Hurler’s syndrome. The project is divided into three sections with 6 milestones in total. The plan is to move from dCPEC process development to lead candidate engineering and selection, and finally to preclinical testing in the mouse model. Objective and Milestones - Reviewers identified a major pitfall in Milestone 3 in terms of the engraftment efficiency. It is not really known what the necessary engraftment level is in their animal model. While they assume that there may be 5-10% engraftment currently, it is unclear if this translates into real change in disease phenotype. - There is a lack of metrics associated with the desired product activity. For example, the levels of enzyme secretion necessary for therapeutic benefit as well as the optimal and minimum levels are missing. These are necessary to establish early go/no go criteria prior to animal studies. Rationale and Significance - The rationale for utilizing cells that can secrete therapeutic proteins directly into the cerebrospinal fluid (CSF), bypassing the blood-brain barrier, is strong. However, the applicant does not describe the advantages of cell transplantation versus direct gene therapy of native CPECs. - Successful implementation of the strategy proposed could overcome many of the current limitations of intrathecal enzyme delivery and provide a platform therapy for the treatment of other diseases. Feasibility and Design - The data on functional analysis and integration of dCPECs after intraventricular injection, both in the application and a referenced journal article, were obtained after only a short follow up. These data fail to support the claim of stable integration of transplanted cells, a key component of the proposed strategy. - The mouse model, while permissive for xenotransplantation, provides no information on the potential allogeneic immune barrier to this approach. While the PI states that most patients will be on an immunosuppressive regimen, the potential for immune rejection should be assessed. - A minimum specification for TALEN recombination should be set. There should be more extensive integration site analysis and determination of the rate of “off target” effects if the goal is to limit insertion to a precise locus. - Some reviewers raised concerns about potential epigenetic silencing of the inserted sequences while others thought that the proposed locus should permit robust expression. All agreed that testing for the possibility of gene silencing should be included in the research plan. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - It is unclear whether the research team possesses appropriate expertise in the area of targeted gene therapy. - The presence of an industry collaborator increased reviewer enthusiasm for the proposal. Collaborations, Assets, Resources and Environment - Appropriate collaborations are in place and the environment is conducive to the work planned. - Appropriate intellectual property assets appear to be held by the applicant and industry collaborator. Responsiveness to the RFA - The proposal is responsive to the objectives of the RFA.