CRISPRa-Engineered Human Neural Stem Cell Therapeutics to Overcome Remyelination Failure in MS
Abstract
Multiple Sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system, affecting more than 2 million people worldwide. It is characterized by focal area of demyelination leading to reversible episodes of neurologic disability that can relapse over time (relapsing-remitting MS). The clinical course usually leads to disease progression over time (secondary and primary progressive MS), causing impaired mobility and cognition and profoundly affecting patients quality of life. Remyelination can occur but tends to decrease with progression, in particular, in older patients with limited regenerative capability. Available therapies are mainly aimed at modifying the frequency and accrual of relapses while treatments aimed at halting disease progression or at repairing pre-existing damages are under evaluation. Among them, neural stem cell (NSC) transplantation is an attractive strategy due to the capability of NSC to ameliorate the inflammatory environment and to replace lost myelin-producing oligodendrocytes. This, coupled with robust data on MS animal models, allowed human fetal NSC to reach clinical evaluation. However, NSC transplantation is limited by the need of large-scale production and immunosuppression. Moreover, the hostile environment of MS lesions impairs the capability of endogenous NSC and oligodendrocyte progenitors to establish at the lesion area and replace damaged cells and myelin, possibly affecting also transplanted cells. Hence, the possibility to enhance NSC properties by promoting secretion of molecules with anti-inflammatory and neuroprotective functions, as well as factors promoting NSC differentiation into myelin-competent cells, could overcome the remyelination failure typical of MS. Moreover, the use of alternative sources to obtain NSC, like pluripotent stem cells that can be directly obtained from the same patient, or derived from universal donors, could overcome the limits of human fetal NSC. Given this premise, the proposed research project will exploit the possibility of genetically modifying human pluripotent stem cell-derived NSC using state-of-the-art gene editing systems to enhance their therapeutic potential, endowing them with an inducible anti-inflammatory/neuroprotective activity and myelinogenic potential, which will be assessed in relevant in vitro and in vivo models. The proposed research project could benefit patients with progressive MS, in which neurodegeneration becomes predominant and still represents an unmet clinical need, as well as patients in the early stages of disease, in which lesions are characterized by significant inflammation. Upon transplantation, engineered NSC could be induced to dampen inflammation and promote restoration of damage that, otherwise, could lead to permanent loss of myelin. This dual mode of action may suggest the use of engineered NSC to halt disease progression, particularly for primary progressive MS. The results obtained by the proposed research project would lay the groundwork for the long-term goal of developing MS-tailored cell products that could support available treatments to reduce neurodegeneration and brain damage thus greatly affecting patients’ quality of life. We are aware that it is a long road ahead for the use of NSC therapies for MS and several fundamental questions need to be answered before their application: (i) safety assessment of pluripotent stem cell-derived products; (ii) production of standardized clinical-grade NSCs; (iii) safety evaluation of therapeutic gene expression; (iv) dosage/route of administration; (v) long-term follow-up of transplanted cells. Nevertheless, we believe that exploiting and enhancing the potential of NSC therapeutics is a research area of great interest and could speed up the translation from bench to bedside in MS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210825
Entities
People
- Marco Luciani
Organizations
- San Raffaele Hospital
- United States Army