Table 3 |.

Candidate disease-modifying drugs for treatment of SCAs

SCA type	Candidate drug	Scientific premise	Preclinical study	Comments
SCA1	MSK1 inhibitor	Inhibitors of the RAS–MAPK–MSK1 pathway decrease levels of ATXN1 and alleviate neurodegeneration in cellular and animal models of SCA1 (REFS68,69)	Further screening and optimization is ongoing	Strong scientific premise. Rigorous preclinical studies are planned. No relevant human clinical observations
SCA1	Stereotactic AAV-mediated delivery of miRNA-like RNAi	RNAi suppresses polyglutamine-induced neurodegeneration in an SCA1 mouse model196. Therapeutic benefits after RNAi expression vector delivery to deep cerebellar nuclei197	RNAi prevents and reverses phenotypes induced by mutant human ATXN1 (REF.198)	Preclinical study is ongoing in B. Davidson’s laboratory under the NIH CREATE BIO199 grant support, which mandates rigorous preclinical study designs and go/no-go milestones200
SCA2	Dantrolene	Inhibits intracellular Ca2+ release and protects Purkinje cells from cell death in the SCA2–58Q mouse model201	Feeding SCA2–58Q mice with dantrolene alleviated age-dependent motor deficits (beam-walk and rotarod assays)201	Modest scientific premise. Needs rigorous preclinical studies. No relevant human clinical observations
SCA3	Dantrolene	Inhibits intracellular Ca2+ release and protects neuronal cells in pontine nuclei and substantia nigra regions from cell death in SCA3-YAC-84Q transgenic mice202	Feeding SCA3-YAC-84Q transgenic mice with dantrolene improved their motor performance202	Modest scientific premise. Needs rigorous preclinical studies. No relevant human clinical observations
SCA3	Citalopram	Identified in an unbiased screening for inhibition of mutant ATXN3 aggregation and reduction of ATXN3 neurotoxicity through neuronal serotonin pathways in cell and animal models70	Efficacy of citalopram was verified in multiple SCA3 transgenic animal models, with chronic treatment leading to decreased neuronal ATXN3 aggregates, astrogliosis, weight loss and motor dysfunction70	Strong scientific premise. Good preclinical studies in two independent laboratories. No relevant human clinical observations
SCA3	Aripiprazole	Identified in an unbiased screen of FDA-approved drugs for reduction of the level of mutant ATXN3 in a cell-based assay71	Not yet done	Unknown mechanism(s) of the effect on the mutant ATXN3. Needs rigorous preclinical studies in SCA3 animal model(s). No relevant human clinical trials or observations
SCA3	Lentiviral delivery of allele-specific203 and allele-nonspecific204,205 siRNA against Atxn3 in a rat model	Silencing of Atxn3 mitigates degeneration in rat. Suppression of wild-type Atxn3 has no adverse effects and allele-nonspecific silencing might be beneficial in rat203–205	Further preclinical studies are needed	Strong scientific premise for targeting the mRNA of the mutant ATXN3. Therapeutic efficacy shown in the rat model needs to be replicated in mouse models. Needs rigorous preclinical studies in SCA3 animal models. No relevant human clinical trials or observations
SCA3	Stereotactic AAV delivery of miRNA	RNAi suppresses ATXN3 levels and alleviates molecular phenotype in SCA3 mouse models206,207	RNAi has induced no behavioural changes	Strong scientific premise for targeting the mRNA of the mutant ATXN3. Needs rigorous preclinical studies in SCA3 animal models. No relevant human clinical trials or observations
SCA1, SCA2 and SCA3	ASO against ATXN1, ATXN2 or ATXN3	In these SCAs, toxic gain-of-function mechanisms are well established. Targeting the mRNA containing toxic polyglutamine expansion is supported by a strong rationale2	Reduction of mutant ATXN2 (REF.208) and ATXN3 (REF.209) mRNA by ASO treatment, and skipping of CAG- repeat-containing exon 10 of ATXN3 (REF.210), are promising therapeutic approaches	Strong scientific premise for targeting the mRNA of the mutant ATXNs. Needs rigorous preclinical studies in animal models of SCA. No relevant human clinical trials or observations
SCA6	miR-3191–5p	In SCA6, the CAG expansion is found in the second cistron (α1ACT) of CACNA1A. miR-3139 attenuates IRES-driven translation of toxic α1ACT66	AAV9–miR-3191–5p protected α1ACT-Q33 mice from ataxia, motor deficits and Purkinje cell degeneration66	Toxic mutant mRNA is the target. Needs rigorous preclinical studies in SCA6 animal models. No relevant human clinical trials or observations
SCA7	Direct delivery of AAV or miRNA to retina in an SCA7 mouse model211	In SCA7, toxic gain-of-function mechanisms are well established2,3. Targeting of the mRNA containing a toxic polyglutamine expansion is supported by a strong rationale. Eyes are severely affected in SCA7 and are readily accessible for delivery of miRNA211	Non-allele-specific suppression of ATXN7 levels was accompanied by preservation of retinal function in SCA7 mice	Both wild-type and mutant ATXN7 mRNA are targeted. Needs rigorous preclinical studies in SCA7 animal models. No relevant human clinical trials or observations
SCA7	Direct delivery of AAV or miRNA to cerebellum of a mouse model of SCA7 (REF.212)	In SCA7, toxic gain-of-function mechanisms are well established. Targeting of the mRNA containing a toxic polyglutamine expansion is supported by a strong rationale	Non-allele-specific suppression of ATXN7 levels was accompanied by improvement of ataxic phenotype in SCA7 mice	Both wild-type and mutant ATXN7 mRNA are targeted. Needs rigorous preclinical studies in SCA7 animal models. No relevant human clinical trials or observations

α1ACT, α1A carboxyl terminus; AAV, adeno-associated virus; ASO, antisense oligonucleotide; ATXN, ataxin; CREATE BIO, Cooperative Research to Enable and Advance Translational Enterprises for Biotechnology Products and Biologics; IRES, internal ribosome entry site; MAPK, mitogen-activated protein kinase; miRNA, microRNA; MSK1, nuclear mitogen and stress-activated protein kinase 1; RNAi, RNA interference; SCA, spinocerebellar ataxia; siRNA, small interfering RNA.