Translating cell therapies for neurodegenerative diseases: Huntington’s disease as a model disorder

Abstract

There has been substantial progress in the development of regenerative medicine strategies for central nervous system disorders over the last decade, with progression to early clinical studies for some conditions. However, there are multiple challenges along the translational pipeline, many of which are common across diseases and pertinent to multiple donor cell types. These include defining the point at which the preclinical data are sufficiently compelling to permit progression to the first clinical studies; scaling-up, characterization, quality control and validation of the cell product; design, validation and approval of the surgical device; and operative procedures for safe and effective delivery of cell product to the brain. Furthermore, clinical trials that incorporate principles of efficient design and disease specific outcomes are urgently needed (particularly for those undertaken in rare diseases, where relatively small cohorts are an additional limiting factor), and all processes must be adaptable in a dynamic regulatory environment. Here we set out the challenges associated with the clinical translation of cell therapy, using Huntington’s disease as a specific example, and suggest potential strategies to address these challenges. Huntington’s disease presents a clear unmet need, but, importantly, it is an autosomal dominant condition with a readily available gene test, full genetic penetrance and a wide range of associated animal models, which together mean that it is a powerful condition in which to develop principles and test experimental therapeutics. We propose that solving these challenges in Huntington’s disease would provide a road map for many other neurological conditions. This white paper represents a consensus opinion emerging from a series of meetings of the international translational platforms Stem Cells For Huntington’s Disease and the European Huntington’s Disease Network Advanced Therapies Working Group, established to identify the challenges of cell therapy, share experience, develop guidance, and highlight future directions, with the aim to expedite progress towards therapies for clinical benefit in Huntington’s disease.

New strategies of neurodegenerative disease treatment with extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs)

“…Real-time monitoring of vector delivery has become the gold standard for gene therapy through MRI-guided convection-enhanced delivery (iMRI-CED) 68 . It would be possible to translate promising preclinical therapies for neurodegenerative disorders into clinical trials if this advanced neurosurgical technique is successfully applied 69 .…”

Human striatal progenitor cells that contain inducible safeguards and overexpress BDNF rescue Huntington’s disease phenotypes in R6/2 mice

“…However, PSC-based therapies are associated with possible safety risks including teratomas, which are a type of tumor that can form from residual undifferentiated PSCs in the therapeutic cell product 23 . Another safety risk is in vivo engraftment of undesired cell types which could occur if the therapeutic cell product contains contaminating cells of a wrong lineage 24 .…”

“…However, PSC-based therapies are associated with possible safety risks including teratomas, which are a type of tumor that can form from residual undifferentiated PSCs in the therapeutic cell product 23 . Another safety risk is in vivo engraftment of undesired cell types which could occur if the therapeutic cell product contains contaminating cells of a wrong lineage 24 . Thus, stem-cell based therapeutic strategies for HD and other neurodegenerative diseases would benefit greatly from using human PSCs (hPSCs) and incorporating safeguards to minimize or eliminate these potential hazards.…”