ARO-ATXN2 for Spinocerebellar Ataxias
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Arrowhead Pharmaceuticals
Disqualifiers: Uncontrolled hypertension, Cardiac, Liver, Renal, others
Trial Summary
What is the purpose of this trial?Adult participants with spinocerebellar ataxia type 2 (SCA2) who carry ≥33 cytosine, adenine, guanine (CAG) repeats in the ATXN2 gene, and who have met all protocol eligibility criteria will be randomized to receive a single dose of ARO-ATXN2 or placebo and be evaluated for safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) parameters.
Do I need to stop my current medications for the trial?
The trial information does not specify whether you need to stop taking your current medications. Please consult with the trial coordinators for more details.
What data supports the effectiveness of the drug ARO-ATXN2 Injection for treating Spinocerebellar Ataxias?
Research on similar treatments, like antisense oligonucleotides (ASOs) targeting the ATXN2 gene in mouse models, shows promise in improving motor function and reducing disease protein levels, suggesting potential effectiveness for ARO-ATXN2 in treating Spinocerebellar Ataxias.
12345Eligibility Criteria
This trial is for adults with spinocerebellar ataxia type 2 (SCA2) who have a specific genetic marker (≥33 CAG repeats in the ATXN2 gene). Participants should not be pregnant or breastfeeding, must have a SARA score ≤14 indicating their disease severity, and normal coagulation levels. They must agree to use effective contraception during the study and for 90 days after.Inclusion Criteria
Non-pregnant, non-lactating
Scale of Assessment and Rating of Ataxia (SARA) score ≤14
Coagulation parameters within normal ranges at Screening
+2 more
Exclusion Criteria
I have a serious heart, liver, or kidney condition.
Human immunodeficiency virus (HIV) infection (seropositive at Screening)
Seropositive for hepatitis B (HBV) or hepatitis C (HCV) at Screening
+5 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single dose of ARO-ATXN2 or placebo and are evaluated for safety, tolerability, pharmacokinetics, and pharmacodynamics
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4-8 weeks
Participant Groups
The trial is testing ARO-ATXN2 Injection versus a placebo in individuals with SCA2. After receiving one dose, participants will be monitored to assess how safe and tolerable the drug is, as well as its effects on the body (pharmacokinetics) and on the disease's progression (pharmacodynamics).
2Treatment groups
Experimental Treatment
Placebo Group
Group I: ARO-ATXN2Experimental Treatment1 Intervention
ARO-ATXN2 Injection
Group II: PlaceboPlacebo Group1 Intervention
(0.9% NaCl)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Research Site 2Montréal, Canada
Research Site 1Montréal, Canada
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Who Is Running the Clinical Trial?
Arrowhead PharmaceuticalsLead Sponsor
References
Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy. [2018]Spinocerebellar ataxia type 1 is one of nine polyglutamine expansion diseases and is characterized by cerebellar ataxia and neuronal degeneration in the cerebellum and brainstem. Currently, there are no effective therapies for this disease. Previously, we have shown that RNA interference mediated silencing of ATXN1 mRNA provides therapeutic benefit in mouse models of the disease. Adeno-associated viral delivery of an engineered microRNA targeting ATXN1 to the cerebella of well-established mouse models improved motor phenotypes, neuropathy, and transcriptional changes. Here, we test the translatability of this approach in adult rhesus cerebella. Nine adult male and three adult female rhesus macaque were unilaterally injected with our therapeutic vector, a recombinant adeno-associated virus type 1 (rAAV1) expressing our RNAi trigger (miS1) and co-expressing enhanced green fluorescent protein (rAAV1.miS1eGFP) into the deep cerebellar nuclei using magnetic resonance imaging guided techniques combined with a Stealth Navigation system (Medtronics Inc.). Transduction was evident in the deep cerebellar nuclei, cerebellar Purkinje cells, the brainstem and the ventral lateral thalamus. Reduction of endogenous ATXN1 messenger RNA levels were ≥30% in the deep cerebellar nuclei, the cerebellar cortex, inferior olive, and thalamus relative to the uninjected hemisphere. There were no clinical complications, and quantitative and qualitative analyses suggest that this therapeutic intervention strategy and subsequent reduction of ATXN1 is well tolerated. Collectively the data illustrate the biodistribution and tolerability of rAAV1.miS1eGFP administration to the adult rhesus cerebellum and are supportive of clinical application for spinocerebellar ataxia type 1.
Treatment of episodic ataxia type 2 with the potassium channel blocker 4-aminopyridine. [2019]Patients with episodic ataxia type 2 (EA2) can often be successfully treated with acetazolamide. The authors report three patients with EA2 (two with proven mutations in the CACNA1A gene) whose attacks were prevented with the potassium channel blocker 4-aminopyridine (4-AP; 5 mg tid). Attacks recurred after treatment was stopped; subsequent treatment alleviated the symptoms (mean follow-up time 6 months). These effects might be due to an improvement of the impaired functioning of Purkinje cells.
Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. [2022]There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.
Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. [2020]The most common dominantly inherited ataxia, spinocerebellar ataxia type 3 (SCA3), is an incurable neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene that encodes an abnormally long polyglutamine tract in the disease protein, ATXN3. Mice lacking ATXN3 are phenotypically normal; hence, disease gene suppression offers a compelling approach to slow the neurodegenerative cascade in SCA3. Here we tested antisense oligonucleotides (ASOs) that target human ATXN3 in two complementary mouse models of SCA3: yeast artificial chromosome (YAC) MJD-Q84.2 (Q84) mice expressing the full-length human ATXN3 gene and cytomegalovirus (CMV) MJD-Q135 (Q135) mice expressing a human ATXN3 cDNA. Intracerebroventricular injection of ASOs resulted in widespread delivery to the most vulnerable brain regions in SCA3. In treated Q84 mice, three of five tested ASOs reduced disease protein levels by >50% in the diencephalon, cerebellum, and cervical spinal cord. Two ASOs also significantly reduced mutant ATXN3 in the mouse forebrain and resulted in no signs of astrogliosis or microgliosis. In Q135 mice expressing a single ATXN3 isoform via a cDNA transgene, ASOs did not result in similar robust ATXN3 silencing. Our results indicate that ASOs targeting full-length human ATXN3 would likely be well tolerated and could lead to a preventative therapy for SCA3.
Tc-99m HMPAO brain SPECT imaging in children with acute cerebellar ataxia. [2016]We prospectively evaluated consecutive cases of acute cerebellar ataxia in children to identify brain perfusion SPECT features associated with acute cerebellar ataxia and to correlate the brain SPECT findings to clinical severity and prognosis.