Clinical trial NCT04419974: Astrocytic Markers and the Pre-ataxic Period of SCA3/MJD - BIGPRO Study Astrocytes
Official title: Biomarkers and Genetic Modifiers in a Study of Pre-ataxic and Ataxic SCA3/MJD Carriers (BIGPRO Study) - Astrocytes
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Spinocerebellar Ataxia Type 3
Machado-Joseph Disease
SCA3
MJD
Keywords: SCA3/MJD
SCA3
MJD
natural history
cytokines
astrocytes
quality of life
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
First posted: 2020-06-09
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals with molecular diagnosis of SCA3/MJD will be recruited from the Medical Genetics Service database of Hospital de Clínicas de Porto Alegre, Brazil, by telephone calls or by invitation in the outpatient clinic. First degree relatives of these subjects at 50% risk of carrying the mutation will also be invited to participate.

Brief summary: The study will consist of a prospective observation of subjects in a natural history design. The investigators will monitor changes of clinical scales, quality of life, messenger ribonucleic acid (mRNA) of candidate genes (CCL11, TNFSF14, FCGR3B, CLC, and SLA) (and their peptide products, when possible), and eotaxin and S100B serum levels, in order to determine which of them is (are) the most sensitive. Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls).

Detailed description: Spinocerebellar ataxia type 3, or Machado-Joseph disease (SCA3/MJD), is an autosomal dominant neurodegenerative disorder caused by a CAG expansion at ATXN3. The gene product is a 42kDa protein called ataxin-3, widely expressed in neurons and peripheral tissues. Physiological roles of ataxin-3 include, at least, ubiquitination and regulation of misfolded proteins, cytoskeletal organization and focal adhesions development, and transcriptional regulation, most often as a transcriptional corepressor. One purpose of the present study is to detect a possible association between altered transcription patterns of candidate genes and disease progression. On the other hand, previous evidences suggest that the disease process linked to polyQ aggregation in neuronal cell ("cell-autonomous process") might be worsened by what happens outside the neuronal cell ("non-cell-autonomous process"). Initial evidences lead to the role of astrocytes. This is a major depart from the traditional understanding of polyglutamine diseases, and comprises the main focus of the present study.

The main hypothesis of this study is that the SCA3/MJD clinical features may be in part associated to astrocytic processes. In order to test it, peripheral level of LIGHT protein (encoded by TNFSF14) and eotaxin (encoded by CCL11) - both expressed in astrocytes -, and of S100B (a myelin damage marker), will be measured. The investigators speculate if they can be biomarkers of disease progression and of pathological process, even before symptoms onset. In case this is positive, their responsiveness to change will be tested to check if it is better than those of clinical scales.

The second aim is to test if disease progression can be associated with changes in the transcriptional pattern of candidate genes FCGR3B, CLC and SLA.

"BIGPRO study - Astrocytes" intends to identify variations in these candidates and validate them as SCA3/MJD biomarkers. The study will consist of a prospective observation of subjects in a natural history design. Changes in clinical scales, quality of life, messenger ribonucleic acid (mRNA) of candidate genes (CCL11, TNFSF14, FCGR3B, CLC, and SLA) (and their peptide products, when possible), and eotaxin and S100B serum levels will be monitored in order to determine which of them is (are) the most sensitive. Participants will be stratified in three groups: ataxic carriers, pre-ataxic carriers and non-carriers (controls). For each asymptomatic carrier, the time until start of disease will be estimated according to the individual CAG expanded sequence (CAGexp) and subject's age. Clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Scale for SCA (NESSCA), International Co-operative Rating Scale (ICARS), Inventory of Non-ataxia Symptoms (INAS), SCA Functional Index (SCAFI), Composite Cerebellar Functional Severity Score (CCFS) and Quality of Life measurements (EQ-5D and SF-36), will be applied at baseline, at 12 months and at 24 months, in all subjects (all three groups). Eotaxin, TNFSF14, S100B and mRNAs, will be measured in the same moments. Progression rates of all these variables will be estimated through mixed-models, including, as covariates, age, group and their interactions.

Eligibility criteria: Inclusion Criteria:

* Individuals with molecular diagnosis of SCA3/MJD
* Individuals at 50% risk of inheriting SCA3/MJD mutation without any clinical manifestation

Exclusion Criteria:

* Refusal to sign informed consent
* Other diagnosed neurological conditions;
* Diabetes Mellitus;
* Chronic allergy (asthma, eczema, urticaria)
* Eosinophilia on baseline

Primary outcomes:
measure: Change in serum concentrations of Eotaxin
timeFrame: 24 months
measure: Change in serum concentrations of S100B
timeFrame: 24 months
measure: Change in expression of TNFSF14
timeFrame: 24 months
measure: Change in expression of CCL11
timeFrame: 24 months
measure: Change in EQ-5D-3L (EuroQoL 5 Domains evaluated in 3 levels)
timeFrame: 24 months
measure: Change in SF-36 (Short-form 36)
timeFrame: 24 months
Secondary outcomes:
measure: Change in expression of FCGR3B
timeFrame: 24 months
measure: Change in expression of CLC
timeFrame: 24 months
measure: Change in expression of SLA
timeFrame: 24 months
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
state: Rio Grande Do Sul
Study officials:
affiliation: Hospital de Clinicas de Porto Alegre
name: Laura B. Jardim, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: