Safety and efficacy evaluation of intracerebroventricular human neural stem cell transplantation in SOD1 mice as a novel approach for ALS.

Background: Neural stem cell (NSC) transplantation holds promising therapeutic potential for neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). However, pre-clinical studies and early-phase clinical trials have faced challenges hindering the effective clinical translation of this approach. Crucial hurdles include the side-effects of prolonged immunosuppression, concerns regarding cell origin and transplantation dosage, identification of the most appropriate therapeutic window, and invasiveness of surgical procedures. Here, we assessed the safety and efficacy of intracerebroventricular (ICV) hNSC transplantation as a novel and possibly more effective experimental approach for ALS.

Methods: We evaluated the safety of administering up to 1 × 10 hNSCs in immunodeficient mice and assessed their potential efficacy in reducing ALS hallmarks employing the SOD1 mouse model. Both transient (15 days) and prolonged immunosuppression regimens, at low (15 mg/kg) and high (30 mg/kg) doses, were tested along with two different cell dosages (3 × 10 and 1 × 10).

Results: Our study suggests that: (i) a bilateral ICV transplantation of 1 × 10 hNSCs is safe and non-tumorigenic in immunodeficient hosts; (ii) sustained and high-dose immunosuppression is essential for ensuring cell survival in immunocompetent SOD1 mice; and (iii) hNSCs may delay motor symptom progression and reduce spinal cord microgliosis in SOD1 mice when administered in the lateral ventricles under prolonged high-dose (30 mg/kg) immunosuppression.

Conclusions: ICV transplantation of hNSCs emerges as a safe and promising strategy for ALS, demonstrating potential to delay motor decline and reduce spinal cord microgliosis. However, sustained high-dose immunosuppression is crucial for therapeutic efficacy, emphasizing the need for further optimization to overcome translational challenges and achieve durable clinical benefits.