Children with inherited degenerative diseases of the brain will be among the first to benefit from novel approaches based on stem cell therapy (SCT). This assertion is based on a number of medical and experimental observations and precedents including:
1) These diseases currently lack effective therapies and can cause profound mental retardation or lead to death;
2) SCT has already been shown to work in the milder forms of similar diseases that do not affect the brain;
3) Experimental work and early clinical studies have clearly shown that stem cells delivered directly into the brain can be used to treat diseases affecting the brain; and
4) The clinical safety of stem cells delivered directly into the brain has already been established during recent Phase 1 clinical trials.
Our approach is designed to lead to a therapeutic development candidate, based on stem cells, by addressing two critical issues: (i) that early intervention is not only required but is indeed possible in this patient population and that, (ii) induction of immune tolerance is also required. We not only address these two important issues but also set the stage for efficient translation of our approach into clinical practice, by adapting transplant techniques that are standard in clinical practice or in clinical trials and using laboratory cell biology methods that are easily transferrable to the scale and processes of clinical cell manufacturing.
We are focusing on a class of childhood brain diseases that causes a child's brain to degenerate and results in severe mental retardation or death, in addition to damage to many other organ systems. These diseases are not yet represented in CIRM’s portfolio. Recently blood stem cell transplantation has been applied to these diseases, showing that some of the organ systems can be rescued by stem cell therapy. Unfortunately, the brain component of the disease is not impacted by blood stem cell therapy. Our team proposes to take these important lessons to develop a therapy that treats all organ dysfunction, including brain. Because of the established stem cell success in the clinical treatment of non-brain organs and the experimental treatment of the brain, we propose a novel, combined stem cell therapy. Based on our own work and recent clinical experience, this dual stem cell therapy has a high probability of success for slowing or reversing disease, and importantly, will not require children to be treated with toxic immunosuppressive drugs. This therapy will thus benefit California by: 1) reducing disease burden in individuals and the State's burden for caring for these children; 2) providing a successful model of stem cell therapy of the brain that will both bolster public confidence in CIRM's mission to move complex stem cell therapies into the clinic; and 3) laying the groundwork for using this type of therapy with other brain diseases of children.
The objective of this Development Candidate (DC) proposal is to develop a stem cell based therapeutic for the treatment of a fatal pediatric lysosomal storage disease that causes neurodegeneration as well as defects in other major organ systems. While hematopoietic stem cell (HSC) transplantation has been demonstrated to ameliorate peripheral symptoms of this disease, it does not treat the neurodegenerative aspects. This team proposes to treat both peripheral and neurodegenerative symptoms using a dual stem cell transplant approach that also avoids the need for pharmacologic immunosuppression. This proposal includes five milestones: 1) derivation and characterization of therapeutic neural stem cells (NSC) and finalization of a good laboratory practice (GLP) protocol for good manufacturing practices (GMP) production; 2) quantification of the ability of HSC transplantation to decrease glycosaminoglycan levels and improve function of major organ systems; 3) quantification of NSC transplant effect on brain pathology; 4) assessment of the ability of dual stem cell transplant to significantly decrease lysosomal storage disease pathology and extend lifespan in a mouse model; 5) development of a clinical GMP (cGMP) protocol suitable for clinical cell manufacture.
Objective and Milestones
- The TPP outlines a scientifically and clinically reasonable combination therapy "process-based approach" to a severe lysosomal storage disease (LSD). The unmet clinical need has been clearly identified. Preliminary data support rationale and the proposed attributes.
- The objective and aims are focused, complete, logical and achievable in three years.
- There is minimal justification that non-ablative HSC transplantation for LSD patients is the current standard of care.
- The critical assumption that NSC transplantation is safe is questionable.
Rationale and Significance
- The rationale and approach are scientifically compelling. The proposed research leads toward a novel DC. If successfully developed, the DC will have a significant impact on disease.
- Current therapy for this disease is not curative, and there is still a significant unmet medical need to better impact/prevent the neurodegenerative processes in this disease. Obviating the need for chronic immunosuppression would also be a significant advance.
- In preliminary experiments, immune-competent mice apparently did not reject transplanted NSCs, negating one of the claimed benefits of matching NSC and HSC transplantation.
Research Project Feasibility and Design
- The research plan is focused, well designed, and, in conjunction with the preliminary results, addresses all activities necessary to lead towards a development candidate ready for IND-enabling preclinical development in three years. Potential pitfalls are acknowledged and alternative plans are provided.
- There is no justification for why reprogramming should start with CD34+ enriched cells from the cord blood (as opposed to other cord blood cells).
- A complication with cord blood (CB) transplants is graft versus host disease (GVHD). The goal is to not have immunosuppressive therapy because of matching CB and NSC, but there is still concern about GVHD.
- Some reviewers were concerned that the hematopoietic stem cell transplantation (HSCT) in the mouse model would not lead to immune reconstitution, and therefore that no adequate measure of rejection could be assessed. However, other reviewers felt that this model was not intended to assess rejection, but was only meant to be proof of concept that dual HSCT and NSCT could have significant disease-modifying effect in an animal model.
- Some reviewers recommended that the applicant consider some practical details of the proposed clinical trial. For example, the specific CB unit will have to be selected for appropriate HLA-matching. In addition, the CB unit will arrive cryopreserved in one bag; therefore testing previously cryopreserved blood should be considered. Also, the PI should consider how to take an aliquot of the CB for iPSC generation without compromising the main unit.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The PI is proposing 40% effort, which is a good level of commitment for this complicated project.
- The PI, Co-PI and Partner PI do not appear to have direct product development experience however they have enlisted a consultant with relevant IND experience. The lack of documented achievements in translational research is offset by the progress made to date in identification of cells and early POC studies.
- Together the PI and key members of the team have relevant qualifications, including experience to lead the proposed research project. The budget is sizeable and includes a substantial request for equipment that one would expect to be in place in a well-established laboratory. Also, the request for personnel is high and should be further justified.
Collaborations, Assets, Resources and Environment
- There is a good team of collaborators from other institutions with appropriate knowledge in the specific disease, neuropathology, and engineering.
- Proposed collaborations are critical to the success of the project and evidence of collaborator commitment is presented.
- Assets, resources and environment appear adequate to conduct proposed research.
Responsiveness to the RFA
- Human stem cells are necessary to develop the proposed therapeutic for this disease.
- Within the context of this proposal iPS derivation is necessary. However, there is a significant question as to whether cord blood cells themselves could directly accomplish similar clinical benefit without the need for the complicated derivation of iPS, followed by differentiation of NSC.
- A motion was made to move this application into Tier 1, Recommended for Funding. A major reason is the need to invest in pediatric diseases. There were no fundamental flaws in the proposal, despite some specific weaknesses with the design. The motion carried.