Children with lethal inherited degenerative diseases of the brain, the lysosomal storage diseases or LSDs, will be among the first to benefit from novel approaches based on stem cell therapy (SCT). This belief is based on a number of medical and experimental observations including:
1) These diseases cause profound mental retardation or lead to death in most affected children;
2) SCT has already been shown to work in the milder forms of LSD that do not affect the brain;
3) The clinical safety of neurotherapy by stem cell transplantation is already being established in the LSDs;
4) Many of the pertinent regulatory hurdles have already been overcome; and
5) Experimental work has clearly shown that SCT can be used to treat the brain in the severe forms of LSD.
This combination of medical and experimental data strongly suggest that the LSDs are uniquely poised to benefit from novel SCT and that this therapy is likely to be successful, a prediction that can less reliably be made for SCT applied to other brain and spinal cord diseases and injuries. Additionally, results of clinical trials of novel stem cell neurotherapies for the LSDs will be directly pertinent to proposed stem cell neurotherapies for some other neurological diseases, including Alzheimer’s disease, Parkinson's disease, multiple sclerosis, and stroke, as specific targets for these and other brain and spinal cord diseases and injuries are better identified.
Our approach is designed to lead to a therapeutic development candidate, based on stem cells, by addressing two critical issues: that adequately repairing a damaged brain is likely to be extremely difficult or impossible and that, as in all cell, tissue, or organ transplantation, immune rejection of the transplanted material is almost guaranteed. We not only address these two important issues but also set the stage for efficient translation of our approach into clinical practice because almost all of it is based on techniques that are already in clinical practice or in clinical trials.
Statement of Benefit to California:
We are focusing on a class of childhood brain diseases that causes the child's brain to degenerate and results in severe mental retardation or death. These diseases also affect other organs of the body. Many of these organs can already be successfully treated with stem cell therapy. Our team proposes to take these lessons of success and apply them to treating the brain as well. Because of this established stem cell success, this new stem cell therapy, we propose, has a high probability of success. This will not only provide a potential cure for the children that are treated with this new stem cell therapy, but will also benefit California by 1) reducing the State's burden for caring for these children and 2) providing a successful model of stem cell therapy of the brain that will both bolster public confidence in CIRM's mission to move stem cell therapies into the clinic, and lay the groundwork for using this type of therapy with other brain diseases such as Alzheimer's disease, Parkinson's disease, stroke, and multiple sclerosis.
This is a development candidate (DC) award application that focuses on the use of combined hematopoietic stem cell transplantation (HSCT) and neural stem cell (NSC) transplantation for the treatment of lysosomal storage diseases (LSDs). LSDs are rare inherited enzyme deficiencies that have both peripheral and central neurologic manifestations. Transplanted cells are thought to provide a source of the missing enzyme and alleviate symptoms of the disease. Clinical use of HSCT to treat LSDs has provided beneficial effects only in those patients that do not have central nervous system (CNS) disease involvement. The applicant hypothesizes that co-transplantation of NSCs and HSCT will address both the CNS and peripheral manifestations of the disease. The applicants propose to use induced pluripotent stem cell (iPSC) technology to derive immune-matched NSCs from the same source as the HSCs and carry out systemic HSCT (Aim 1), CNS transplantation (Aim 2), and combined HSCT/NSC transplantation in a preclinical murine model of LSD.
The objectives in this proposal are focused and technically achievable and the basic rationale is justified in LSD. Reviewers appreciated the innovative concept and relevance to stem cell research. Reviewers agreed that although targeting a rare disease, the proposal, if successful, could impact the standard of care for these patients as well as impact treatment of other central nervous system (CNS) disorders, although they noted that it may be difficult to prove additive or synergistic benefit over HSCT or enzyme replacement therapy.
Despite their appreciation of the conceptual basis of this proposal, reviewers had several concerns regarding feasibility. In particular, they were concerned that the proposed studies would not result in a development candidate ready to enter preclinical IND-enabling studies at the end of the funding period. Key experiments addressing critical issues such as appropriate therapeutic dose; preliminary tumorgenicity; immune response to the secreted enzyme; and persistence, location and function of NSCs were neglected. Reviewers were particularly concerned that testing of a single dose to assess both safety and efficacy is very problematic and that the inclusion of enzyme replacement therapy confounds assessment of efficacy in the model. They noted that it is important to understand the dose response for each cellular component and the impact of enzyme replacement therapy on efficacy. A dose response is of further importance given that a margin of safety around the efficacious dose is required to address tumorgenicity. iPSC characterization should include at a minimum teratoma formation and repeated karyotyping. There was limited consideration of cell production issues. It is unclear from the proposal what reagents are available as GMP reagents for NSC enrichment or what level of enrichment will be required to prevent tumor formation.
The reviewers also noted that translation of the approach will prove challenging. First, the applicant did not address practical concerns such as the need to obtain a single donor unit with sufficient numbers of cells to permit isolation of HSC and of cells for iPSC generation as well as the likely substantial delay in treatment of CNS disease due to the need to generate iPSC-derived NSCs and obtain sufficient numbers for therapeutic injection. Second, the applicant will perform the stem cell transplants simultaneously in immune-deficient LSD mice, and reviewers were concerned that the proposed preclinical model and treatment approach does not adequately model the clinical situation and provide a strong basis for large animal studies. Specifically, the immune-deficient mouse may not be able to generate an immune response to the produced enzyme; it is likely that a staged approach will be required in the clinic where patients do not receive both the HSCT and the CNS transplantation simultaneously; and treatment of mice that have not yet accumulated the enzyme substrate does not closely mimic the human situation where substrate accumulation is generally present by the time treatment is initiated. The reviewers noted that the therapeutic relevance of the proposed studies would be significantly increased had the applicant proposed to treat adult mice where substrate accumulation has already occurred.
The Principal Investigator (PI) is experienced in the proposed area of science and will commit a substantial percent of his/her time to this proposal, although a biographical sketch for the PI was not included in the submission. The co-PI is excellent and this team has an outstanding track record in LSD and is clearly capable of accomplishing the research goals. Reviewers did note that there are a substantial number of positions requiring specialized skills that are listed as “to be hired” and were concerned that this might present a significant delay in initiating the research studies.
Although reviewers thought this proposal to be very good conceptually and appreciated the quality of the team, they agreed that due to the absence of several key studies and an experimental design that does not adequately model the clinical situation, this proposal is unlikely to result in a development candidate that is ready to enter into IND-enabling preclinical research within the timeframe of the award.