Table 2.

Huntingtin-lowering programs targeting DNA and RNA

Compound	Stage of development (study ID)	Delivery	Advantages	Disadvantages	Clinical results
DNA-targeting approaches
Zinc-finger transcription factor
Takeda/Sangamo NOS [52]	Preclinical	Intracranial*	Single treatment can provide long-term effects Applicable to all HD mutation carriers May cover all pathogenic mechanisms	Invasive delivery Irreversible effect Restricted diffusion in the brain Immunogenicity of nonhost protein	n/a
Imperial College London [53, 54]	Preclinical	Intracranial*	Same as above Lesser immunogenic effect, with use of host species proteins	Invasive delivery Irreversible effect Restricted diffusion in the brain	n/a
CRISPR/Cas9
Emory University [55]; University of Pennsylvania [56]; Harvard University [57]	Preclinical	Fibroblasts [55, 56] Intrathecal [57]	Highly specific and targeted May cover all pathogenic mechanisms	Irreversible effect Ethical concerns Invasive delivery Immunogenicity of bacterial proteins Effect on germline	n/a
RNA-targeting approaches
Antisense oligonucleotide
RG6042/tominersen	Phase Ia/2 (NCT02519036)	Intrathecal	Applicable to all HD mutation carriers	Unknown risks of wild-type HTT Repeated lumbar punctures	First-in-human study Safe and well-tolerated [58]
RG6042/tominersen	Phase III (NCT03761849)	As above	As above	As above	Ongoing Recruitment concluded
WVE-120101; WVE-120102	Phase Ib/2a (NCT03225833; NCT03225846)	Intrathecal	Target mutant allele	Applicable to a group of HD mutation carriers (SNP-specific) Repeated lumbar punctures	Preliminary results: safe and mean reduction of 12.4% in CSF mHTT [59]
Biomarin NOS	Preclinical	Intrathecal	Target mutant allele with a single drug for all HD mutation carriers	Greater risking of off-target effects Repeated lumbar punctures	n/a
RNA interference
AMT-130 (miRNA)	Phase I/II (NCT04120493)	Intracranial*	Nonselective miRNA Single treatment can provide long-term effects	Invasive delivery Irreversible effects Restricted diffusion in the brain Neutralizing antibodies	n/a
VY-HTT01 (miRNA)	Preclinical	Intracranial*	As above	As above	n/a
Spark NOS	Preclinical	Intracranial*	As above	As above	n/a
ALN-HTT (siRNA)	Preclinical	Implantable pump for intracranial infusion system	–	–	n/a
Small-molecule splicing modulators
PTC-CHDI NOS	Preclinical	Oral	Ease of delivery Potentially reversible	Nonselective approach targeting total HTT Off-target effects	n/a
Skyhawk-Novartis NOS	Preclinical	Oral	–	–	n/a

NOS = not otherwise specified; n/a = not available

*Adeno-associated virus (AAV) as a vector