Multimodal human induced pluripotent stem cell (hiPSC)-based therapy for childhood neurodegenerative lysosomal storage diseases
Early Translational IV
$2 121 294
Lysosomal storage diseases (LSDs) are due to defects in enzymes that normally degrade fats and other cellular substances that are no longer useful. Not only are cells unable to get rid of this waste but also the toxic byproducts that build up can kill nerve cells, leading to harmful symptoms. The symptoms reflect what organ is directly affected, be it bone marrow (effecting blood production), liver, or spleen. Sometimes the affected region comprises the brain and spinal cord. For most affected organs, treatment includes replacing the missing enzyme or gene (in other words, gene therapy) or performing a bone marrow transplant to replace the defective cells. Afflicted organs not helped by these therapies include the brain and spinal cord due to the blood brain barrier, which acts like a brick wall to block therapeutic substances injected into the bloodstream from accessing the brain. Hence, nerve cells die, resulting in devastating symptoms such as those involved with movement, speech, memory, thinking, and personality. In our work, we hypothesized that if we transplanted cells directly into the brain, we could circumvent the blood brain barrier and deliver active proteins to damaged nerve cells to compensate for the defective proteins, and we would have a good chance to defeat these diseases.
Statement of Benefit to California:
As a group, lysosomal storage disorders affect about 1 in 7500 live births but this estimate is likely low as increasing numbers of individuals with mild and/or adult-onset forms of the diseases are being identified. Either way, treating this disease group is a major challenge for California’s healthcare system, extracting a heavy burden in terms of patients mortality and quality of life (progressive neurodegeneration and mental impairment), along with steep economic costs from labor-intensive and often unsuccessful treatments. No therapy exists to treat these diseases. We hope to turn around a major obstacle that is limiting the potential success of neural stem cell therapies—limited neural stem cell migration, specifically those stem cells derived from human induced pluripotent stem cells (IPSC-NSCs). The stable, benign peptide SDF-DV1 aids hIPSC-NSCs migration by harnessing the fundamental biology of stem cell pathotropism without triggering inflammation. Success in this arena stands to benefit the larger community of California neuroscience disease researchers who are working to bring their stem cell therapies to patients suffering from a wide range of debilitating neurological diseases that may extend beyond those of LSDs and those germane to early childhood.
This application for a Development Candidate Feasibility (DCF) award is focused on a combination cell and protein therapy for lysosomal storage disease (LSD). The applicant proposes to develop gene-corrected neural stem cells (NSCs) from induced pluripotent stem cells (iPSCs) derived from Sandhoff disease patients, along with a protein to enhance NSC migration in the brain. Sandhoff disease is a rare, genetic, neurodegenerative LSD that predominantly affects children. The proposed gene correction will enable the NSCs to produce the functional enzyme that is missing in these patients. The applicant proposes to test iPSC-derived NSCs, together with the protein, in a mouse model of Sandhoff disease. Proposed milestones include generation of gene-corrected iPSCs and NSCs, transplantation of cells and protein into two relevant animal models, and assessment of functional improvement and cell migration. Objective and Milestones - The target product profile (TPP) does not make clear the product envisioned for clinical use in humans. The TPP refers repeatedly to preclinical animal testing and there is virtually no mention of genetic modification of iPSC-derived NSCs. In addition, minimally acceptable and optimal product activities are not defined. - The milestones lack clear go/no go decision points and success criteria. Reviewers noted an absence of metrics defining success or failure of the proposed studies. Rationale and Significance - The rationale for transplantation of gene-corrected iPSC-derived NSCs in Sandhoff disease is sound. Further, the rationale for using a protein to enhance cell homing is logical and could be applied toward other therapeutic indications. - Reviewers were not sure how well the mechanism of action of the protein would scale to the human brain as the distances cells will have to migrate are much larger. - Reviewers described the proposed gene transduction method as suboptimal due to random site integration. Targeted gene correction methods are available and would strengthen the scientific rationale for the approach. - LSDs are a class of disabling and often lethal genetic diseases for which there is a high unmet medical need. If successful, this project could have implications for LSDs in addition to Sandhoff disease. Feasibility and Design - Reviewers were not convinced that immune rejection of transplanted human NSCs would not be a problem in the proposed animal models. They noted that cell rejection could impact the duration of response and compromise interpretation of in vivo data. Reviewers recommended the use of immunocompromised or immune suppressed animal models. - Reviewers questioned the value of the studies proposed in the newborn, non-diseased animal model. They noted that cell survival and migration may be very different in this model than in a Sandhoff patient. - Methods for generating the proposed development candidate are poorly described. - Reviewers questioned the plan to move into a second animal model without first performing dose finding studies. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The PI lists no publications since 2009. Reviewers were concerned by this recent lack of productivity and the PI’s minimal experience leading a research team. - The presence of three established collaborating scientists adds to the quality of the research team. Collaborations, Assets, Resources and Environment - The institutional resources re excellent. - Relevant intellectual property is not described. Responsiveness to the RFA - The application is responsive to the RFA.