Lombardi Ivan, Ferrero Clelia, Vulcano Edvige, Rasà Daniela Maria, Gelati Maurizio, Pastor Diego, Carletti Rose Mary, de la Morena Silvia, Profico Daniela Celeste, Longobardi Sabrina, Lazzarino Elisa, Perciballi Elisa, Rosati Jessica Diana, Martinez Salvador, Vercelli Alessandro, Vescovi Angelo Luigi, Boido Marina, Ferrari Daniela
School of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.
J Transl Med. 2025 May 9;23(1):529. doi: 10.1186/s12967-025-06529-9.
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.
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).
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.
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.
神经干细胞（NSC）移植对于肌萎缩侧索硬化症（ALS）等神经退行性疾病具有潜在的治疗前景。然而，临床前研究和早期临床试验面临着阻碍该方法有效临床转化的挑战。关键障碍包括长期免疫抑制的副作用、对细胞来源和移植剂量的担忧、确定最合适的治疗窗口以及手术的侵入性。在此，我们评估了脑室内（ICV）人神经干细胞（hNSC）移植作为一种新型且可能更有效的ALS实验方法的安全性和有效性。
我们评估了在免疫缺陷小鼠中给予高达1×10个hNSC的安全性，并使用SOD1小鼠模型评估了它们在减少ALS特征方面的潜在疗效。测试了低剂量（15mg/kg）和高剂量（30mg/kg）的短期（15天）和长期免疫抑制方案，以及两种不同的细胞剂量（3×10和1×10）。
我们的研究表明：（i）在免疫缺陷宿主中，双侧ICV移植1×10个hNSC是安全的且不会致瘤；（ii）持续的高剂量免疫抑制对于确保免疫健全的SOD1小鼠中的细胞存活至关重要；（iii）在长期高剂量（30mg/kg）免疫抑制下，当在侧脑室中给予hNSC时，hNSC可能会延迟SOD1小鼠的运动症状进展并减少脊髓小胶质细胞增生。
hNSC的ICV移植成为一种安全且有前景的ALS治疗策略，显示出延迟运动功能衰退和减少脊髓小胶质细胞增生的潜力。然而，持续的高剂量免疫抑制对于治疗效果至关重要，强调需要进一步优化以克服转化挑战并实现持久的临床益处。
