A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis

Maier, Marcel; Welt, Tobias; Wirth, Fabian; Montrasio, Fabio; Preisig, Daniel F.; McAfoose, Jordan; Vieira, Fernando; Kulic, Luka; Späni, Claudia; Stehle, Thilo; Perrin, Steve; Weber, Markus; Höck, Christoph; Nitsch, Roger M.; Grimm, Jan

doi:10.1126/scitranslmed.aah3924

Cited by 72 publications

(67 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…40 Researchers from Neurimmune (Schlieren, Switzerland) recently reported the development of a fully human antibody against amyotrophic lateral sclerosis targeting pathologically misfolded SOD1, α-miSOD1, from a memory B-cell library from healthy elderly individuals. 41 Phase III trials involving aducanumab, a bona fide human antibody with potent β-amyloid clearing capabilities, were stopped prematurely. 42 In previous works, we found that anti-PrP C antibodies can efficaciously counteract prions, 6 a finding later confirmed by several other researchers.…”

Section: Discussionmentioning

confidence: 99%

Autoantibodies against the prion protein in individuals with PRNP mutations

Frontzek

Carta

Losa³

et al. 2020

Neurology

View full text Add to dashboard Cite

ObjectiveTo determine whether naturally occurring autoantibodies against the prion protein are present in individuals with genetic prion disease mutations and controls, and if so, whether they are protective against prion disease.MethodsIn this case–control study, we collected 124 blood samples from individuals with a variety of pathogenic PRNP mutations and 78 control individuals with a positive family history of genetic prion disease but lacking disease-associated PRNP mutations. Antibody reactivity was measured using an indirect ELISA for the detection of human immunoglobulin G1–4 antibodies against wild-type human prion protein. Multivariate linear regression models were constructed to analyze differences in autoantibody reactivity between (1) PRNP mutation carriers vs controls and (2) asymptomatic vs symptomatic PRNP mutation carriers. Robustness of results was examined in matched cohorts.ResultsWe found that antibody reactivity was present in a subset of both PRNP mutation carriers and controls. Autoantibody levels were not influenced by PRNP mutation status or clinical manifestation of prion disease. Post hoc analyses showed anti-PrPC autoantibody titers to be independent of personal history of autoimmune disease and other immunologic disorders, as well as PRNP codon 129 polymorphism.ConclusionsPathogenic PRNP variants do not notably stimulate antibody-mediated anti-PrPC immunity. Anti-PrPC immunoglobulin G autoantibodies are not associated with the onset of prion disease. The presence of anti-PrPC autoantibodies in the general population without any disease-specific association suggests that relatively high titers of naturally occurring antibodies are well-tolerated.Clinicaltrials.gov identifierNCT02837705.

show abstract

Section: Discussionmentioning

confidence: 99%

Autoantibodies against the prion protein in individuals with PRNP mutations

Frontzek

Carta

Losa³

et al. 2020

Neurology

View full text Add to dashboard Cite

show abstract

“…Hence, repeated tests of the same mouse is feasible, which enables longitudinal studies of drug efficacy with a powerful statistical design in which individual subjects are compared to themselves over time. Therapies that target patients with mutations of the SOD1 gene have successfully completed early clinical study phases, and have prolonged survival in SOD1 related animal models 27,28 . Microendoscopy measurements in animal models given these drugs should be performed to understand the effects of the drug on motor unit distribution over time in individuals, and further validate the measurement method.…”

Section: Scientific Reports |mentioning

confidence: 99%

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

Chen

Sanchez

Schnitzer

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal disease involving motor neuron degeneration. Effective diagnosis of ALS and quantitative monitoring of its progression are crucial to the success of clinical trials. Second harmonic generation (SHG) microendoscopy is an emerging technology for imaging single motor unit contractions. to assess the potential value of microendoscopy for diagnosing and tracking ALS, we monitored motor unit dynamics in a B6.SOD1G93A mouse model of ALS for several weeks. prior to overt symptoms, muscle twitch rise and relaxation time constants both increased, consistent with a loss of fast-fatigable motor units. These effects became more pronounced with disease progression, consistent with the death of fast fatigue-resistant motor units and superior survival of slow motor units. From these measurements we constructed a physiological metric that reflects the changing distributions of measured motor unit time constants and effectively diagnoses mice before symptomatic onset and tracks disease state. these results indicate that SHG microendoscopy provides a means for developing a quantitative, physiologic characterization of ALS progression.ALS is a paralytic, fatal neurodegenerative disease characterized by a progressive loss of motor neurons 1 . The first approved drug to treat ALS, riluzole, which only prolongs survival by a few months 2 , was approved over 20 years ago. Since then, over 50 clinical trials 3 have resulted in only 1 new recently approved drug 4 , edaravone, whose effect on survival has yet to be studied. Development of effective treatments has suffered from a lack of methods for early diagnosis and sensitive monitoring of the disease 5 . Patients enter clinical trials at late disease stages that may be too advanced to gain therapeutic benefit, and subtle improvements might be undetectable. Sensitive diagnostics are needed to reduce diagnostic delay so that earlier-stage patients can be identified and participate in clinical trials.To assess if a therapy is effective, it is also important to have biomarkers of disease progression. Currently, the Revised ALS Functional Rating Score (ALSFRS-R) -a numerical score from 0-48 based on assessments of bulbar, limb, and respiratory function 6 -is the predominant clinical method for measuring disease progression. This score is subjective and a sum of multiple metrics, some of which are highly correlated, making changes in the ALSFRS-R score hard to relate to changes in disease state 7 . As new candidate treatments enter clinical trials, the field needs quantitative diagnostics that reflect the neurophysiologic changes in ALS, provide accurate assessments of disease progression, and inform treatment development and usage.To meet this challenge, we examined whether second harmonic generation (SHG) microendoscopy might detect the physiological changes that occur in ALS. SHG microendoscopy is a minimally invasive approach to imaging the twitch contractions of individual motor units in live patients 8 . Myosin filaments within muscle sar-

show abstract

“…Misfolded protein aggregates, including some containing SOD1, are a well-described feature of ALS (27)(28)(29). One research group used a computer modeling program to predict that resveratrol would reduce SOD1 protein aggregates (30).…”

Section: Protein Aggregationmentioning

confidence: 99%

ALSUntangled no. 49: resveratrol

2019

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

View full text Add to dashboard Cite

ALSUntangled reviews alternative and off-label therapies on behalf of persons with amyotrophic lateral sclerosis (PALS). Here, we review the use of resveratrol in PALS for which we have received over 550 votes (1). Overview Resveratrol is the common name for the chemical compound known as trans-3,5,4'-trihydroxystilbene. It can be naturally found in small quantities in wine, grapes, berries, and peanuts (2,3). Resveratrol has been studied in a myriad of human diseases including cancer, diabetes, obesity, and neurodegenerative diseases and is commonly thought to be a sirtuin activator (see "mechanisms"; 3-5). It is difficult to study in vitro and in cell culture due to its ability to interfere with some commonly used biochemical assays. This assay interference can potentially lead to results that falsely suggest therapeutic benefits (6,7). Therefore, we will primarily focus on evidence obtained from animal and human trials in this review. Mechanisms There are several ways resveratrol could potentially benefit PALS including modulating sirtuins, inhibiting protein aggregation, and altering the gut microbiome. Sirtuins Sirtuins are a family of enzymes we discussed in a previous ALSUntangled review (8). Sirtuin 1

show abstract

A human-derived antibody targets misfolded SOD1 and ameliorates motor symptoms in mouse models of amyotrophic lateral sclerosis

Cited by 72 publications

References 54 publications

Autoantibodies against the prion protein in individuals with PRNP mutations

Autoantibodies against the prion protein in individuals with PRNP mutations

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

ALSUntangled no. 49: resveratrol

Contact Info

Product

Resources

About