Stem Cell Mediated Therapy of Genetic Degenerative Childhood Disorders-Particularly Neurodegenerative Lysosomal Storage Diseases

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00715
Investigator: 
ICOC Funds Committed: 
$0
oldStatus: 
Closed
Public Abstract: 
Progress in the use of stem cells for therapies depends on matching the known biological repertoire of the stem cell with the known etiologies of a given disease. For most diseases & for most aspects of stem cell biology, these are unknown. However, certain lethal childhood neurological diseases, e.g., some lysosomal storage diseases (LSDs) fit into this category. Not only are they excellent models for learning about stem cells, but these are devastating childhood diseases without cure. They can also serve as models for more complex & less well-understood adult & childhood diseases. Although childhood maladies are often forgotten by the stem cell field, we believe that such disorders may be the “low-hanging fruit” in the stem cell field for proving efficacy & safety, for honing our craft & extending our knowledge, & for beginning to fulfill some of stem cell’s therapeutic promise. LSDs typically are characterized by a missing enzyme because the infant is born with a defective or absent gene. While we have become successful in reversing some disease manifestations outside the brain by supplying the missing enzyme, it has been difficult to get the enzyme into & throughout the brain at sustained levels because of the blood-brain barrier. Stem cells, particularly those that have been turned into immature neural cells, can circumvent this barrier & actually become permanent parts of normal brain structure. Furthermore, they manufacture the missing enzyme as part of their natural repertoire. In addition, they have other therapeutic actions -- they are anti-inflammatory & protective. Finally, although they can become neurons, they more readily become an equally valuable cell type – “chaperone” cells that protect imperiled host neurons. In animal models of LSDs, these multiple actions have dramatically extended life & preserved function. Given the complexities of brain development, preserving established circuitry is as important as, & probably more tractable than attempting to reconstruct new connections. In infantile disorders such as these, if treatment is instituted early enough – a possibility enabled by prenatal/neonatal screening -- irretrievable brain damage might be averted. Our multidisciplinary team will attempt to pave the way to a clinical trial using the best stem cells available from a range of potential sources (embryonic, fetal or adult brain, bone marrow, reprogrammed cells, amniotic fluid cells, umbilical cells) that will emulate in children with Tay-Sachs & Sandhoff Diseases our success in mice. The team will work out the logistics of cell preparation, animal model analysis, patient selection & monitoring, & whether adjunctive therapies may work synergistically with the cells. We anticipate at least 1 clinical trial within 3 years which, in turn, will serve as proof-of-concept for other diseases.
Statement of Benefit to California: 
Progress in the use of stem cells for therapies depends on matching the known biological repertoire of the stem cell with the known etiologies of a given disease. For most diseases & for most aspects of stem cell biology, these are unknown. However, certain lethal childhood neurological diseases, e.g., some lysosomal storage diseases (LSDs) fit into this category. Not only are they excellent models for learning about stem cells, but these are devastating childhood diseases without cure. They can also serve as models for more complex & less well-understood adult & childhood diseases. Although childhood maladies are often forgotten by the stem cell field, we believe that such disorders may be the “low-hanging fruit” in the stem cell field for proving efficacy & safety, for honing our craft & extending our knowledge, & for beginning to fulfill some of stem cell’s therapeutic promise (& the promise of Prop. 71). Children with inborn error of metabolism that are untreated will either die or persist into a chronically disabled mentally retarded infantile condition that requires lifelong intense care. The prevalence of these diseases is 1 in 5000 births in California. If left untreated -- & most are heretofore untreatable, particularly if they involve the brain -- the societal drain is enormous in many ways: (a) costly state-supported care at specialized facilities; (b) having a disabled, high-maintenance dependent child at home usually insures that 1 parent -- typically a young, productive wage-earner -- cannot be in work force; (c) having such a child at home often disrupts functioning of the family unit (increasing the rate of divorce & the chances that otherwise healthy siblings become emotionally unhinged, requiring counseling & special schools). Conversely, “saving” a child may allow him/her to contribute to society for the next 50-60 years. Encouragingly, in infantile disorders such as these, if treatment is instituted early enough – a possibility enabled by prenatal/neonatal screening -- irretrievable brain damage might be averted. Our multidisciplinary team will attempt to pave the way to a clinical trial using the best stem cells available in order reproduce in children our success in mice. The chances of success in infants is enhanced (perhaps greater than in adults) because the stem cell, which is actually a component of normal developmental programs, may harness developmental processes still operative n the prenatal/neonatal human brain. Indeed, if successful, one might contemplate treating certain adult diseases in their more receptive pediatric pre-symptomatic phase (e.g., Huntington’s), perhaps making the ultimate adult expression of the disease much more benign. We anticipate at least 1 clinical trial within 3 years for an LSD which, in turn, will serve as proof-of-concept for other childhood & adult diseases. Such novel approaches could also give rise to new intellectual property, in which California would be a stakeholder.

© 2013 California Institute for Regenerative Medicine