AN UPDATE ON MULTIPLE SYSTEM ATROPHY

Abstract

Purpose of review:

Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an update on α-synuclein’s role in MSA pathophysiology and review the new Movement Disorders Society (MDS) diagnostic criteria and the utility of α-synuclein-based biomarkers. We also highlight ongoing efforts toward clinical trial readiness and review potential disease-modifying therapies undergoing clinical trials.

Recent findings:

A role of urinary tract infections in triggering α-synuclein aggregation and contribution of genes implicated in oligodendroglial development have been suggested in the MSA pathophysiology. The clinically probable MSA category of the new diagnostic criteria shows improved accuracy in early disease stages. Predictors of phenoconversion from pure autonomic failure to MSA are now better defined. Alpha-synuclein strains in CSF and serum, phosphorylated α-synuclein deposits in the skin, and brain α-synuclein pathology visualized using PET ligand [18F]ACI-12589 are emerging as valuable diagnostic tools. Clinical trials in MSA investigate drugs targeting α-synuclein aggregation or preventing α-synuclein expression, along with stem cell and gene therapies to halt disease progression.

Summary:

New MSA diagnostic criteria and α-synuclein-based biomarkers may enhance diagnostic accuracy while promising therapies are in development to address disease progression.

Introduction

Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disease characterized by parkinsonism, cerebellar ataxia, pyramidal signs and dysautonomia in any combination.(1, 2) At disease onset, the predominant motor phenotype is either parkinsonian (MSA-P) or cerebellar (MSA-C). With disease progression, however, most patients show a combination of both cerebellar and parkinsonian features. Pathologically, MSA is defined by widespread oligodendroglial cytoplasmic inclusions (GCIs) containing misfolded phosphorylated α-synuclein along with neuronal loss and gliosis in striatonigral and olivopontocerebellar structures. Age at onset is usually in the 6th decade with rapid progression to severe disability within 5–6 years and death within 10 years.(3)

Genetics

The molecular basis of MSA remains unknown; it is primarily considered a sporadic disease with no clear environmental or genetic risk factors identified. However, notable exceptions exist, particularly in certain familial cases with confirmed MSA pathology and autosomal dominant or recessive inheritance pattern observed in European and Asian pedigrees.(4) One puzzling genetic finding in MSA involves functionally impaired variants of the COQ2 gene. This gene encodes an enzyme crucial for the biosynthesis of coenzyme Q10 (CoQ10). Studies in familial and sporadic cases from Japan have linked CoQ2 variants to MSA.(5) Reduced CoQ10 levels in the brain tissue of COQ2 variant carriers and in the CSF and blood of sporadic MSA cases have been noted. This discovery prompted a clinical trial of ubiquinol, an oral CoQ10 supplement. A small clinical benefit was reported, suggesting a role of CoQ10 in the pathophysiology of MSA.(6) These results await further validation and replication in larger studies.

Moreover, a recent genome-wide association study (GWAS) highlighted a risk locus at the GAB1 gene, which plays a role in oligodendroglial development. Additionally, a recessive association model revealed a borderline significant signal at the KCTD7 gene with significant enrichment of rare missense mutations observed. These findings suggest a potential genetic basis for MSA implicating genes involved in oligodendroglial function and development.(7) Another recent GWAS study in post-mortem confirmed MSA cases identified a variant in close proximity of ZIC1 and ZIC4 which encode transcription factors critical for cerebellum development. Further immunohistochemical analysis showed reduced ZIC4-immunoreactive neurons in patients with olivopontocerebellar atrophy suggesting ZIC4-mediated neuronal vulnerability in MSA.(8)

α-synuclein role

α-Synuclein is a 15kDa intracellular protein found in brain neurons, astrocytes, microglia, and oligodendroglia, peripheral nerves, and blood cells. For unknown reasons α-synuclein can aggregate and misfolds to form fibrils and oligomers, which are neurotoxic. The central events in the pathophysiology of synucleinopathies, specifically the aggregation of misfolded α-synuclein into neurotoxic oligomers, protofibrils and fibrils, as well as the formation of intracellular aggregates and its propagation, remains incompletely understood. In PD and DLB, α-synuclein aggregates form in neurons as Lewy bodies and Lewy neurites. Conversely, in MSA, α-synuclein aggregates primarily as glial cytoplasmic inclusions (GCIs) within oligodendrocytes, with secondary neuronal degeneration.(3)

The structure of α-synuclein aggregates differs between MSA and Lewy body diseases. In MSA, GCIs are composed of two types of filaments, each comprising two distinct protofilaments. This structural arrangement contrasts with the composition of α-synuclein aggregates in PD and DLB. Moreover, MSA-specific α-synuclein strains exhibit higher seeding potential and distinct conformations compared to α-synuclein found in PD and DLB. The distinct molecular properties of MSA-specific α-synuclein likely contribute to the unique clinical features and disease progression seen in MSA compared to PD and DLB.(9, 10)

One intriguing hypothesis regarding MSA pathogenesis involves the potential role of bacterial urinary tract infections (UTI) in triggering abnormal aggregation of endogenous α-synuclein in autonomic nerves innervating the bladder. Neurogenic bladder with increased post-void residual urine and frequent UTI are common in patients with prodromal MSA. Studies in mice have shown that urinary tract infection results in de novo aggregation and release of α-synuclein from neutrophils. Furthermore, injection of α-synuclein aggregates into the bladder of mice that overexpress oligodendroglial α-synuclein have shown the propagation of α-synuclein pathology to the central nervous system and progressive development of synucleinopathy with oligodendroglial involvement.(11)

Can we diagnose MSA earlier?

MSA is typically diagnosed several years into the disease and many patients remain misdiagnosed during life preventing proper counseling and inclusion into clinical trials.(12) The new MDS diagnostic criteria for MSA were developed to improve accuracy and achieve earlier diagnosis.(13) (Table 1).(14) The clinically probable MSA category has higher sensitivity and manifest earlier than clinically established MSA category which also includes brain MRI biomarkers. A new research category of possible prodromal MSA was defined to capture patients at earliest disease stages when motor symptoms are incipient. Criteria for possible prodromal MSA are autonomic failure (neurogenic orthostatic hypotension or neurogenic bladder with high post-void residual) and REM sleep behavior disorder associated with subtle motor signs. This category will be crucial for recruitment in clinical trials of disease-modifying drugs when they become available. Polysomnography, smell test and cardiac MIBG scintigraphy help in the diagnosis of possible prodromal MSA, while other ancillary investigations are listed as supportive due to their limited availability, need for validation or suboptimal diagnostic accuracy, but clinicians are encouraged to perform these tests if available (Table 1).

Table 1.

MDS criteria for the diagnosis of multiple system atrophy (Modified from Poewe et al., 2022 with permission)(3)

• A sporadic disease with an age at onset of > 30 years • Neuropathologically established MSA is defined by widespread and abundant central nervous system α-synuclein-positive GCIs in association with neurodegenerative changes in striatonigral or olivopontocerebellar structures. • Clinically established MSA is defined as autonomic failure (post void urinary residual volume > 100 ml, urinary urge incontinence or ≥ 20/10 mmHg BP drop within 3 minutes in the upright position) and at least one of poorly L-dopa responsive parkinsonism and cerebellar syndrome (≥ 2 clinical features of cerebellar impairment). Presence of ≥ 2 supportive clinical features and ≥ 1 brain MRI marker and an absence of exclusion criteria are required. • Clinically probable MSA is defined as at least two of autonomic dysfunction (post void urinary residual volume, urinary urge incontinence or ≥ 20/10 mmHg BP drop within 10 minutes in the upright position), parkinsonism and cerebellar syndrome (≥ 1 clinical feature of cerebellar impairment). Presence of ≥ 1 supportive clinical feature and an absence of exclusion criteria are required.

• Supportive clinical features:  • Motor: rapid progression, postural instability, severe speech impairment and dysphagia within 3 years of motor onset, craniocervical dystonia in the absence of limb dyskinesia, Babinski sign, jerky myoclonic postural or kinetic tremor and postural deformities  • Non-motor: stridor, inspiratory sighs, cold discolored hands and feet, erectile dysfunction and emotional incontinence

• Brain MRI markers:  • For MSA-P: atrophy of putamen, MCP, pons and cerebellum, increased diffusivity of putamen and MCP and hot cross bun sign  • For MSA-C: atrophy of putamen, MCP and pons, increased diffusivity of putamen and hot cross bun sign

• Exclusion criteria include clinical or MRI evidence of an alternative condition such as PD, DLB, PSP, other causes of sporadic ataxia and genetic MSA look-alike disorders.

• Possible prodromal MSA is defined as at least one of polysomnography proven REM sleep behavior disorder, ≥20/10 mmHg blood pressure drop within 10 minutes in the upright position and urogenital failure (erectile dysfunction in males <60 years and voiding difficulties with post void urinary residual volume >100 ml and/or urinary urge incontinence), at least one of subtle parkinsonian and cerebellar signs and absence of at least one of unexplained anosmia or abnormal cardiac 123I-MIBG-scintigraphy and of other clinical or MRI evidence suggestive of an alternative MSA look-alike condition.

Supportive biomarkers suggestive of MSA but not required for the MSA diagnosis

These are laboratory findings suggestive of MSA obtained using brain FDG-PET, cardiac 123I-MIBG-scintigraphy, polysomnography, urodynamic testing, sphincter EMG, and measurements of supine plasma norepinephrine, CSF α-synuclein oligomers and plasma and CSF NfL. They are currently not included in the criteria due to their limited availability, suboptimal diagnostic accuracy, or lack of diagnostic validation.

BP: blood pressure; DLB: dementia with Lewy bodies; EMG: electromyography; FDG-PET: fluorodeoxyglucose positron emission tomography; MCP: middle cerebellar peduncle; MRI: magnetic resonance imaging; MSA-P: multiple system atrophy-parkinsonian type; MSA-C: multiple system atrophy-cerebellar type; NfL: neurofilament light chain; PD: Parkinson’s disease; PSP: progressive supranuclear palsy; RBD: REM sleep behaviour disorder; ¹²³I-MIBG: ¹²³I-meta-iodobenzylguanidine

Performance of Movement Disorders Society MSA criteria in early disease stages has been validated against neuropathological diagnosis in the Queen Square Brain Bank series of 318 cases.(15) Within 3 years from onset, the clinically probable MSA category outperformed (sensitivity: 62.1%, specificity: 95.3% and accuracy: 84.6%) clinical diagnosis by experts and both probable and possible MSA categories of the previous consensus criteria.(15, 16) The clinically established category had 100% specificity at the expense of low sensitivity in early disease stages.(15) Validation of possible prodromal MSA category will require prospective long-term follow-up with postmortem diagnostic confirmation.

Pure autonomic failure (PAF) has been identified as a prodromal stage of MSA, PD and DLB. Predictors of phenoconversion are now better defined (Figure 1). Degeneration of nigrostriatal fibers as visualized on DaTScan in patients with PAF may predate clinical signs of CNS involvement.(17) Cardiac 18F-dopamine positron emission tomography may assist in predicting the type of phenoconversion of PAF; PAF patients with diminished cardiac 18F-dopamine radioactivity tend to progress to Lewy body disease, while patients with normal radioactivity either remain in the PAF phase or phenoconvert to MSA.(18)

Figure 1.

Predictors of phenoconversion of pure autonomic failure to MSA

bpm: beats per minute, CSF: cerebrospinal fluid, HR: heart rate, NE: norepinephrine, NfL: neurofilament light chain, pg/ml: picograms per milliliter, ThT: thioflavin

In a large prospective multicenter study, among 209 patients with PAF with median disease duration of 6 years at baseline, 33% phenoconverted to centrally manifest synucleinopathy within 3 years after enrollment. The estimated annual risk of phenoconversion was 12% per year. Factors associated with faster phenoconversion were urinary and sexual dysfunction, subtle motor signs, swallowing and speech problems. Patients phenoconverting to MSA were younger at PAF onset, with preserved olfaction, anhidrosis and severe urinary problems, while those phenoconverting to PD had impaired handwriting and blunted heart rate increase.(19)

α-Synuclein-based biomarkers in the differential diagnosis of MSA

α-Synuclein-based biomarkers are emerging as valuable tools for improving the accuracy of differential diagnosis in MSA, addressing a critical need in clinical practice. Pathological α-synuclein strains in CSF can be visualized using seed amplification assays (SAA) such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). A pooled sensitivity of 88% and specificity of 95% of SAA to differentiate between synucleinopathy from non-synucleinopathy was reported in a meta-analysis.(20) Different maximum fluorescence and kinetics of α-synuclein aggregation among patients with synucleinopathies were demonstrated using PMCA. Samples from MSA patients aggregate faster but reach a lower fluorescence plateau compared to those from patients with PD.(21) In contrast to >90% pooled sensitivity and specificity for differentiation between Lewy body disorders and non-synucleinopathies, the pooled sensitivity for MSA diagnosis dropped to 30% for RT-QuIC, although remained high for PMCA (80 – 97%), which might be explained by the use of different reaction buffers in RT-QuIC and PMCA and structural differences of MSA-specific α-synuclein strains.(20, 22) In patients with PAF, PMCA could perfectly delineate patients who later develop MSA from those who phenoconverted to Lewy body disease or from non-converters based on differences in maximum fluorescence and reaction kinetics.(23)

The pathogenic β-sheet seed conformation of α-synuclein was identified in the serum of patients with MSA and other synucleinopathies employing a modified assay system termed immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC). This technique allows the detection of amplified seeds with maintained disease-specific properties and differentiation of samples from MSA and PD.(24)

Using immunostaining of cutaneous sympathetic nerves, 98% of patients with MSA showed positive phosphorylated α-synuclein deposition. Compared to other synucleinopathies, the localization of deposits within subepidermal plexus was more common in MSA.(25) MSA “signature” in the skin included normal small sensory afferents, normal sympathetic innervation of vascular smooth muscle and greater deposition with even distribution of phosphorylated α-synuclein in the neck, proximal tight, distal thighs.(26)

Recently, α-synuclein pathology in the brain of MSA patients was identified in vivo using a PET ligand. This ligand [18F]ACI-12589 showed good α-synuclein binding properties in vivo binding in cerebellar white matter and middle cerebellar peduncles of MSA patients but limited binding in patients with PD.(27) These biomarkers may contribute to improved diagnostic accuracy, facilitating early and targeted intervention strategies for MSA patients.

Outcome measures for clinical trials of potential disease-modifying drugs

The unified multiple system atrophy rating scale (UMSARS)(28) is currently the preferred primary endpoint for clinical trials of putative disease-modifying treatments, but it has several limitations.(29) To overcome these limitations, two dedicated task forces have been convened, by the National Institutes of Health in 2021 (U01NS122419) and more recently by the MDS, to develop improved patient-centered outcome measures specifically designed to be used in clinical trials. In addition to patient reported outcomes, biomarkers of disease progression are a critical requirement for assessing disease-modifying interventions. Significant brain volume loss over 12 months with cerebellar, pontine, and putaminal volumes being the most sensitive to change has been reported in MSA.(30) Almost two-fold higher effect size of brain atrophy in susceptible brain regions compared to the effect size of UMSARS progression, and the correlation of clinical progression with imaging progression suggest that progressive brain atrophy predates clinical progression and should be used as a biomarker in clinical trials.(31) The inclusion of MRI as an outcome measure would allow smaller sample sizes to achieve statistical power in clinical trials.(32)

Disease-modifying treatments

Several clinical trials intended to slow or arrest disease progression conducted in the past decade have failed to demonstrate efficacy (see Table 2). There is renewed optimism, however, as several promising therapies are now under development. These therapies target different phases of α-synuclein aggregation or prevent α-synuclein expression. Also, clinical trials are testing intrathecal stem cells and one trial is using gene therapy delivering a complementary gene to the glial cell line-derived neurotrophic factor (GDNF) protein directly into the putamen.

Table 2.

Potential disease modifying therapies for MSA

Drug Name	Mechanism of Action	Sponsor	Phase	Status	Comments
Aggregation Inhibitors
ATH-434	Iron Chelator	Alterity Therapeutics	Phase 2	Ongoing
KM-819	FAF1 Inhibitor	Kainos Medicine Inc.	Phase 2	Ongoing
ONO-2808	S1P5 Receptor Agonist	Ono Pharmaceutical co. Ltd	Phase 2	Ongoing
IkT-148009	Abl-Kinase Inhibitor	Inhibikase Therapeutics, Inc.	Phase 2a	Upcoming
EGCG	Alpha-synuclein oligomer modulator	University of Munich	Phase 3	Completed	Not effective
Anle138b	Alpha-synuclein oligomer modulator	TEVA, MODAG	Phase 1	Completed	Confirmed safety
Antisense Oligonucleotide
ION-464	ASO	Ionis Pharmaceuticals, Inc.	Phase 1	Ongoing
Degradation Inhibitors
Rifampicin	Inhibits alpha-synuclein fibrils	Mayo Clinic	Phase 3	Terminated	Futility criteria met
Rapamycin (sirolimus)	mTOR inhibitor	NYU Langone Health	Phase 2	Terminated	Futility criteria met
Lithium Carbonate	Reduces alpha-synuclein aggregation	Federico II University	Phase 2	Terminated	Futility criteria met
Gene Therapy
AAV2-GDNF	Gene therapy	AskBio, Inc.	Phase 1	Ongoing
Immunotherapy
Lu AF82422 (AMULET)	Monoclonal antibody	Lundbeck	Phase 2	Ongoing
TAK-341	Monoclonal antibody	Takeda	Phase 2	Ongoing
UB-312	Vaccine	Vaxxinity	Phase1/2	Ongoing
PD01A/PD03A	Vaccine	Affiris AG	Phase 1	Completed	Confirmed safety
Neuroinflammation
BHV3241 (Verdiperstat)		Biohaven Pharmaceutical, Inc.	Phase 3	Completed	Not effective
Stem Cell Therapy
hOMSC300 Allogenic Human oral Mucosa	Mesenchymal stem cells	Crytora Ltd.	Phase 1/2	Ongoing
Autologous mesenchymal stem cells	Mesenchymal stem cells – Adipose	Mayo Clinic	Phase 2	Ongoing
Autologous mesenchymal stem cells	Mesenchymal stem cells – Adipose	Mayo Clinic	Phase 2	Ongoing
Autologous mesenchymal stem cells	Mesenchymal stem cells – Bone Marrow	Yonsei University	Phase 1	Completed	Confirmed Safety
CS10BR05 Autologous mesenchymal stem cells	Mesenchymal stem cells – Bone Marrow	Corestemchemon, Inc.	Phase 1	Completed	Confirmed Safety

Several promising disease-modifying treatments targeting different phases of α-synuclein aggregation or preventing α-synuclein expression are in development, alongside investigations into intrathecal stem cells and gene therapy directly targeting the putamen. ASO: Antisense oligonucleotide

Immunotherapy.

Active immunotherapy stimulates the body’s own antibody production and passive immunotherapy involves infusing monoclonal antibodies targeting specific antigens. In patients with MSA, active immunotherapies use α-synuclein antigen vaccine to induce the synthesis of anti-misfolded α-synuclein antibodies, whereas passive immunotherapies require intravenous infusions of monoclonal antibodies against misfolded α-synuclein. With both methods antibodies can target α-synuclein aggregates in peripheral neurons and are also able to cross the blood-brain barrier to bind with synuclein in the brain. There are currently four clinical trials using immunotherapies for MSA.

Active immunotherapy.

UB-312 is a synthetic α-synuclein peptide vaccine that induces antibody production against α-synuclein aggregates. UB-312 uses the novel synthetic vaccine carrier platform UBITh T-helper peptide linked to a specific 10-residue C-terminal epitope of α-synuclein that selectively targets oligomer and fibril forms of α-synuclein.(33, 34) In guinea pigs, UB-312 induced prolonged immunity against misfolded α-synuclein fibrils and oligomers, but, importantly, no effect on monomers.(35) A phase 1b randomized placebo control delayed start clinical trial of UB-312 in MSA is currently ongoing (NCT05634876).

PD01A and PD03A (AFFITOPE) are synthetic peptide vaccines for targeting α-synuclein in diseases like Multiple System Atrophy (MSA). Mimicking the α-synuclein C-terminal epitope, they stimulate a B-cell immune response. Coupled with keyhole limpet hemocyanin and an aluminum hydroxide adjuvant, they promote a durable immune defense against misfolded α-synuclein.(36, 37) Phase 1 trials in early MSA patients (NCT02270489) confirmed their safety and tolerability.(38)

Passive immunotherapy.

Lu AF82422 is an anti-α-synuclein human monoclonal antibody (IgG1) that targets the C-terminal end of misfolded α-synuclein.(39) Lu AF82422 can recognizing all major forms of α-synuclein and inhibit the seeding of extracellular pathological aggregations.(40) By inhibiting the spread of toxic forms of α-synuclein to other cells Lu AF82422 should delay disease progression. A recently completed Phase II clinical trial in MSA has shown promising results (NCT05104476).

TAK-341 is a high-affinity monoclonal antibody targeting the C-terminal epitope of monomeric and aggregated forms of α-synuclein.(41) TAK-341 enters the CNS, sequesters misfolded α-synuclein in the interstitial fluid, and blocks cellular uptake of aggregated α-synuclein.(41) A phase II clinical trial in patients with MSA is ongoing (NCT05526391).

Antisense Oligonucleotides (ASOs).

ASOs are short single-stranded synthetic DNA or RNA molecules that bind to complementary target nucleic acids to alter protein or gene expression.(42) ION-464, previously BIIB101, is an ASO that targets α-synuclein mRNA in the SNCA gene to block α-synuclein production.(43) Hopefully, by reducing the synthesis of α-synuclein there will be fewer proteins to misfold and aggregate into mutant forms. One challenge, however, is determining the appropriate degree of treatment. α-synuclein has a role in neurotransmission,(44) therefore a complete knock-out would be harmful. Animal models have shown ASOs to decrease the overall amount of α-synuclein in the CSF and brain tissue, suggesting neuroprotective effects.(45) An ongoing phase I study of ASO ION-464 use a multiple-ascending-dose to evaluate its safety and tolerability in patients with MSA (NCT04165486).

Gene Therapy.

Gene therapy uses a non-infectious virus (vector) to transport genetic alteration therapy to target cells to replace missing or problem-causing genes, turn off problem-causing genes, or add new genes. AAV2-GDNF uses an adeno-associated virus serotype 2 (AAV2) vector that binds to specific brain cells to transport a complementary gene to the glial cell line-derived neurotrophic factor (GDNF) protein.(46) GDNF is a naturally occurring growth factor that plays an important role in the regeneration and survival of the dopaminergic nigrostriatal pathway.(47) An ongoing clinical trial uses neurosurgery with MRI guidance to deliver AAV2-GDNF directly into the putamen of patients with MSA-P to promote survival and continuous function of dopamine-producing cells (NCT04680065).(48)

Aggregation Inhibitors.

Aggregation inhibitors are small molecules that disrupt the formation of α-synuclein oligomers at different stages of production.

ATH-434, formerly known as PBT434, is a quinazolinone compound that inhibits iron-mediated aggregation of α-synuclein, reducing toxic forms and iron accumulation. Preclinical studies in MSA models showed decreased α-synuclein aggregates and neuroprotection.(49, 50) Two ongoing phase II trials (NCT05864365, NCT05109091) investigate ATH-434 in MSA patients.

Patients with PD and MSA show increased levels of FAS-association factor 1 (FAF1), a protein linked to cell death.(51) High FAF1 levels hinder autophagy and lead to α-synuclein buildup in the brain.(52, 53) KM-819, an inhibitor of FAF1, reduces α-synuclein accumulation in dopaminergic neurons.(54) A phase II trial for MSA is underway (NCT05695378).

IkT-148009 (Risvodetinib) is a selective inhibitor of non-receptor Abelson Tyrosine Kinase (c-Abl), an enzyme linked to oxidative stress.(55, 56) Activated c-Abl leads to α-synuclein phosphorylation, causing CGI aggregation and dopaminergic neurodegeneration.(57) IkT-148009 inhibits brain c-Abl, indicating its ability to cross the blood-brain barrier. (58) An upcoming phase IIa clinical trial is planned.

Anle138b, a diphenyl pyrazole compound with high-affinity binding to structural isotopes, binds to neurotoxic α-synuclein aggregations and reduces the number of intermolecular hydrogen bonds in the oligomer.(59) This destabilizes aggregates and prevents the formation of oligomer pores into the cell membrane reducing prion-like seeding and leading to a reduction in CGIs.(60) MSA mouse models treated with Anle138b found decreased levels of α-synuclein and preserved dopaminergic neurons.(61) A phase 1 trial in healthy subjects and patients with PD showed Anle138b to be safe and well tolerated (NCT03208152).(62)

The sphingosine-1-phosphate (S1P) pathway plays an important role in synaptic transmission and cell survival by promoting autophagy.(63) Studies have found plasma S1P levels in patients with MSA to be lower than controls.(64) ONO-2808 is a small molecule S1P receptor agonist that appears to prevent the accumulation of misfolded α-synuclein in oligodendrocytes by enhancing the activity of S1P. ONO-2808 is being studied in an ongoing phase II clinical trial (NCT05923866).

Stem cell therapy.

Transplanted neural stem cells expressing brain-derived trophic factor can modulate dopamine levels, suggesting potential neuroprotective effects.(65) Two phase 1 studies utilized bone marrow-derived autologous mesenchymal stem cells in patients with MSA and both showed safety and tolerability (NCT03265444; NCT00911365).(66) Two ongoing trials are now investigating autologous adipose-derived mesenchymal stem cells for MSA patients (NCT05167721; NCT0231527). Another ongoing trial focuses on an allogenic human oral mucosa mesenchymal stem cell product, hOMSC300 (NCT05698017).

Conclusion

Accurate diagnosis during early and even prodromal stages and the development of disease-modifying interventions to slow disease progression remain crucial unmet needs in MSA. Validating the new diagnostic criteria’s possible prodromal MSA category and assessing diagnostic biomarkers particularly α-synuclein-based ones in early disease stages, are imperative to establish their diagnostic precision. The establishment of patient-centered outcome measures and the validation of biomarkers for disease progression are essential steps for toward enhancing clinical trial readiness in MSA. While numerous disease-modifying treatments targeting α-synuclein aggregation and expression are in progress, other approaches such as intrathecal stem cell therapy and gene therapy using vectors for genetic alteration therapy are also under investigation in clinical trials involving MSA patients.

Summary.

• The clinically probable MSA category of the new Movement Disorders Society diagnostic criteria showed superior diagnostic accuracy compared to previous criteria and experts’ diagnoses as validated by postmortem studies.

• Pure autonomic failure is a feature of the new possible prodromal MSA category with identified rates and predictors of phenoconversion to MSA.

• Alpha-synuclein-based biomarkers including CSF and blood α-synuclein strains, skin phosphorylated α-synuclein detection, and visualization of brain α-synuclein deposition using PET show promise in enhancing diagnostic accuracy.

• Developing of improved patient-centered outcome measures and validated disease progression laboratory biomarkers is crucial for evaluating disease-modifying interventions in MSA.

• Several promising disease-modifying treatments that target different phases of α-synuclein aggregation or prevent α-synuclein expression are in development, alongside investigations into intrathecal stem cells and gene therapy directly targeting the putamen.