Multimodal human induced pluripotent stem cell (hiPSC)-based therapy for childhood neurodegenerative lysosomal storage diseases

Funding Type: 
Early Translational IV
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

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.