Preclinical Validation of Multilevel Intraspinal Stem Cell Therapy for Amyotrophic Lateral Sclerosis (ALS) Open Access

Abstract

Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal and relentlessly progressive neurodegenerative disease with a median survival after symptom onset that ranges from 2 to 5 years. The only FDA approved treatment, riluzole, prolongs this survival by a matter of months. Cell therapies for ALS attempt to restore motor function through replacement of neuronal and non-neuronal cells. Multiple clinical trials using this approach are now underway in many countries around the world. The current study tested the spinal cord's tolerance to increasing volumes and numbers of injections in Gottingen minipigs.

Methods: Twenty-five female minipigs received human neural progenitor cell injections using a stereotactic platform device developed by the Emory group. Cell transplantation in groups 1 to 5 (n = 5 pigs each) was undertaken with the intent of assessing the safety of an injection volume escalation (10, 25, and 50 microL) and an injection number escalation (20, 30 and 40 injections). Sensory and motor function, as well as general morbidity was assessed for 21 days. Full necropsy was performed; spinal cords were analyzed for graft survival and microscopic tissue damage.

Results: No mortality or permanent surgical complications were observed within the 21-day study period. All animals returned to preoperative baseline within 14 days, showing complete motor function recovery. The histological analysis of the tissue showed that there was no significant decrease in neuronal density between groups and the engraftment percentage ranged from 11-31% depending on the injection paradigm. However, significant tissue damage was identified when injecting high volumes into the spinal cord (> 25 microL).

Conclusion: This series supports the functional safety of various injection volumes and numbers in the spinal cord, and gives critical insight to important safety thresholds. The results from this study are relevant to all translational programs delivering cell therapeutics to the spinal cord.

Table of Contents

1. Introduction……………………………………………………………..………. 1

2. Background………………………………………………………….....………. 2

3. Methods……………………………………………………………………....…… 8

4. Results…………………………………………………………………….….….. 22

5. Discussion and Conclusions……………………………………………. 26

6. References……………………………………………………………….……… 32

7. Tables and Figures…………………………………………………..……… 44

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Biology, Neuroscience Health Sciences, Medicine and Surgery
Keyword	Transplantation Spinal Safety ALS Stem cell therapy
Committee Chair / Thesis Advisor	Klein, Mitchel, Emory University
Committee Members	McGowan Jr., John E, Emory University

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