Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy

Abstract

Objective: This phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA).

Methods: Utilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS).

Results: Twenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect.

Conclusions: Intrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial.

Classification of evidence: This phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.

Figure 1. Study timeline

Figure 2. MRI illustrating cauda equina findings

Nerve root thickening, clumping, and enhancement in a 64-year-old patient with multiple system atrophy predominantly involving cerebellar impairment 7 weeks after the first of 2 intrathecal injections of 5 × 107 autologous mesenchymal stem cells at the L4/5 interspace. Although the MRI findings were more prominent than seen in most patients, he remained asymptomatic. (A) Axial T2 image at L4/5 shows thickening of several cauda equina nerve roots. (B) Axial T1 image post gadolinium at the same level shows questionable enhancement. (C) Sagittal T2 image of the lumbar spine shows these changes centered at the site of injection with some distortion and nodular thickening of nerve roots.

Figure 3. Spinal fluid protein and cell count

CSF protein (top) and cell count (bottom) before and after mesenchymal stem cell (MSC) injection by dose group. The low-dose group showed no significant change in CSF protein (A) and cell count (D), while medium- and high-dose groups showed a variable increase of both CSF protein (B, C) and cell count (E, F) after MSC injection. Injection time points are shown as arrows, dashed lines show the upper limit of normal for CSF protein and cell count.

Figure 4. Rate of disease progression (Unified MSA Rating Scale [UMSARS])

Rate of disease progression as measured using UMSARS in mesenchymal stem cell (MSC)–treated patients vs the matched control group. UMSARS total (A–C), UMSARS I (D–F), and UMSARS II (G–I) shown as mean and SD of change per month comparing low dose and medium dose to controls (left panels), and change over time per participant in the low-dose (middle panels) and medium-dose group (right panels). Low-dose group = light blue, medium-dose group = dark blue, controls = red.

Figure 5. Nerve growth factor (NGF) response to mesenchymal stem cell (MSC) injections

Spinal fluid NGF levels (mean and SD) before and after intrathecal MSC injection (indicated with arrows). NGF was largely undetectable at baseline, showed a slight but nonsignificant rise after the single MSC injection in the low-dose group (light blue), but was elevated dramatically 1 week after each MSC injection in the medium-dose tier (dark blue), with still markedly elevated levels 4 weeks after each injection.