Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is one of nine polyglutamine expansion diseases and the most common dominantly inherited ataxia in the world. SCA3 is caused by an expansion of a polyglutamine-coding CAG repeat in the ATXN3 gene. Currently, there is no effective treatment for this relentlessly progressive and fatal disease. With the goal of preventive therapy for SCA3, several ongoing studies seek to reduce levels of the disease protein, ATXN3. Our published work with antisense oligonucleotides (ASOs) targeting human ATXN3 provides strong preclinical evidence of gene silencing efficacy in a SCA3 mouse model of disease. As we progress gene silencing and other therapeutics toward the clinic, a necessary hurdle for success is to define robust biomarkers of SCA3 disease that may directly/indirectly assess disease progression and treatment response. To address this gap in the field, we have designed a longitudinal trial that will repeat dose SCA3 mice with a gene silencing treatment beginning at an early symptomatic age and assess noninvasive high field magnetic resonance spectroscopy (MRS) and blood plasma biomarkers repeatedly over one year. These biomarkers will be correlated with disease progression as defined by brain pathology and motor assessment and assess how well the biomarkers reflect gene silencing efficacy in brain tissue. Based on our data with SCA3 gene silencing therapy and MRS in the SCA3 mouse model that expresses the full-length human ATXN3 disease gene, we expect to uncover reliable biomarkers of disease progression that are readily exacerbated by gene silencing therapy and are predicted to translate well to future human trials.
SCA3 is the most common dominantly inherited ataxia worldwide, affecting an estimated 1: 20,000 people. Success from SCA3 therapeutic studies in animal models has increased the urgency for SCA3 disease biomarker discovery. The proposed work is relevant to SCA3 public health as it will define longitudinal quantifiable SCA3 disease biomarkers from both a noninvasive brain imaging technique and blood samples that are rescued upon gene silencing therapy.
