State stem cell agency application DT1-00715-1

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

Recommendation: Not recommended for funding. Recommended to be available for funding only if the ICOC makes a programmatic determination to fund this application
Scientific Score: 69

Total Funds Requested: $55,000

Public Abstract (provided by applicant)

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 (provided by applicant)

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.

Review

This planning award application proposes to put together a team to develop the use of neural stem cell (NSC) transplantation for lysosomal storage diseases (LSDs), which are rare but untreatable childhood diseases resulting from deletions or deficiencies in key enzymatic pathways. In particular Tay Sachs and Sandhoff’s diseases, which are significant clinical targets along with the other LSDs, will be addressed. In this proposal, the applicant proposes to assemble a team to enable a clinical trial using the best stem cells derived from a range of potential sources including: embryonic, fetal or adult brain, bone marrow, reprogrammed cells, amniotic fluid cells and umbilical cells to determine the best candidate for clinical use. In addition, the PI plans to combine this approach with substrate reduction therapy. The concept is that transplanted NSCs may supply the missing enzyme in the diseased brain and also can act through other mechanisms to limit loss of brain function.

Reviewers found the proposal not well organized and very confusing. Moreover, the reviewers found a lack of grantsmanship style as the proposal contained large amounts of information in small pictures and small fonts that made the information very difficult to interpret.

Reviewers recognized the significance of the target, as Tay Sachs and Sandhoff’s diseases are rare but untreatable and fatal genetic diseases. A major obstacle to current treatment has been the inability to circumvent the blood-brain barrier (BBB) in order to deliver persistent, effective levels of the required therapeutic molecules. NSCs seem to have the correct migratory and developmental properties to address these issues. The evidence for this hypothesis is provided by the principal investigator’s (PI) previously published work and in the preliminary data included in the proposal; however, most of the animal work has been done with central nervous system (CNS)-derived NSCs. A strength of the application is the PI’s persuasive argument that the clinical benefit seen in animal models reflects the combination of enzymatic replacement and neuroprotection mediated by the transplanted cells. Given that the animal model closely resembles the human disease, these diseases represent plausible targets. The proof-of-principle studies have advanced the field to a position where translation and clinical trials are a logical next step, and reviewers felt the concept could enter the clinic within the next five years.

However, reviewers discussed several weaknesses which dampened overall enthusiasm for the proposal. The review panel found that the potential risks of transplantation of incompletely differentiated SCs are an essential part of this work and are lacking in this proposal. Moreover, reviewers felt that the proposal lacked adequate consideration of the methodologies to be used to differentiate (or commit) the hESCs prior to transplantation. In this relatively mature clinical concept, reviewers felt that the issues of clinical heterogeneity of the diseases, the ethical issues surrounding transplantation into children, outcome measures for the clinical trials, the likely size of trial required to deliver a clear result and the need for statistical expertise from the earlier stages should have been addressed in the planning approach.

Reviewers agreed that the PI is a strength of the proposal. The PI is a well known thought leader and investigator in the NSC field with a strong track record in publications and extensive experience with cellular therapies in models of the LSDs. S/he has led clinical teams and participated in multiple clinical trials and has the appropriate leadership qualities required to lead this program.

The planning approach was not well organized. Beyond a symposium and monthly meetings, little detail was given as to how the project would be advanced to the clinic. The application lists a large group of scientists and their expertise as the backdrop to how s/he will carry out the planning process toward a clinical application. The team contains excellent scientists and covers most of the areas required for pre-clinical and translational SC medicine. What is less clear is the expertise in clinical trials. This would need to be considered in the next steps of the planning process.

The following Working Group members had a conflict of interest with this application and were therefore recused from participating in review of, discussion of, and voting on the application:

  • Kurtzberg, Joanne
  • Rothstein, Jeffrey