Christina Fournier

Transplantation of spinal cord–derived neural stem cells for ALS Analysis of phase 1 and 2 trials

Objective: To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers. Methods: This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale–Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups. Results: Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression. Conclusions: Intraspinal transplantation of human spinal cord–derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers. Classification of evidence: This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues.

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72-associated amyotrophic lateral sclerosis. Homing in on poly(GP) proteins A mutation in the C9ORF72 gene causes amyotrophic lateral sclerosis (ALS) through the accumulation of G4C2 RNA. Therapeutics that target G4C2 RNA are thus being developed. Testing these therapeutics in patients with “c9ALS” will depend on finding a marker to monitor the effect of treatments on G4C2 RNA. Gendron et al. demonstrate that poly(GP) proteins produced from G4C2 RNA are present in cerebrospinal fluid from c9ALS patients. Furthermore, using patient cell models and a mouse model of c9ALS, they report that poly(GP) proteins correlate with G4C2 RNA, suggesting that poly(GP) could be used to test potential treatments for c9ALS in upcoming clinical trials. There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA–mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA–based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Head injury does not alter disease progression or neuropathologic outcomes in ALS

Objectives: To study the effects of head injury on disease progression and on neuropathologic outcomes in amyotrophic lateral sclerosis (ALS). Methods: Patients with ALS were surveyed to obtain head injury history, and medical records were reviewed. Linear regression was performed to determine if head injury was a predictor for mean monthly decline of Amyotrophic Lateral Sclerosis Functional Rating Scale–revised (ALSFRS-R), while controlling for confounders. Head injury history was obtained from family members of ALS autopsy cases. The frequency of tau proteinopathy, brain TDP-43 inclusions, and pathologic findings of Alzheimer disease (AD) were examined in ALS cases with head injury compared to cases without. Logistic regression was performed with each neuropathologic diagnosis as an outcome measure and head injury as a predictor variable. Results: No difference was seen in rate of decline of the ALSFRS-R between patients with head injury (n = 24) and without (n = 76), with mean monthly decline of −0.9 for both groups (p = 0.18). Of 47 ALS autopsy cases (n = 9 with head injury, n = 38 without), no significant differences were seen in the frequency of tau proteinopathy (11% with head injury; 24% without), TDP-43 in the brain (44% with head injury; 45% without), or AD pathology (33% with head injury; 26% without). Independent logistic regression models showed head injury was not a predictor of tau pathology (p = 0.42) or TDP-43 in the brain (p = 0.99). Conclusions: Head injury was not associated with faster disease progression in ALS and did not result in a specific neuropathologic phenotype. The tau pathology described with chronic traumatic encephalopathy was found in ALS autopsy cases both with and without head injury.

Predicting disease progression in amyotrophic lateral sclerosis

It is essential to develop predictive algorithms for Amyotrophic Lateral Sclerosis (ALS) disease progression to allow for efficient clinical trials and patient care. The best existing predictive models rely on several months of baseline data and have only been validated in clinical trial research datasets. We asked whether a model developed using clinical research patient data could be applied to the broader ALS population typically seen at a tertiary care ALS clinic.

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population.

Objective: We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features. Methods: Between 2001 and 2015, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives. Results: The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank χ2[1] = 45.323, p < 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD. Conclusions: Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.

ALS untangled no. 20: The Deanna protocol

ISSN 2167-8421 print/ISSN 2167-9223 online

Modeling the course of amyotrophic lateral sclerosis

Large-scale computational analysis of patient data leads to better models of disease progression.

Post-lumbar puncture headache is reduced with use of atraumatic needles in ALS

ISSN 2167-8421 print/ISSN 2167-9223 online

Primary lateral sclerosis and early upper motor neuron disease: Characteristics of a cross-sectional population

Objectives: The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Methods: Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Results: Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Conclusions: Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

ALSUntangled: Introducing the table of evidence

We found no precedent for grading the types of evidence we review, so we used a ‘ crowd sourcing ’ approach to create the TOE. One ALSUntangled reviewer (RB) constructed a fi rst draft. The rest of the review team then suggested edits via emails over two months. Finally a subset of reviewers met in person and validated the utility of the TOE by attempting to convert the evidence from all 26 prior ALSUntangled reviews into this.