Future therapies on near horizon for Huntington disease
Presenter: Jee Bang, MD, Johns Hopkins Medicine, Baltimore, MD
Updates in Huntington disease. Presented April 25, 2023
Future therapeutic strategies for Huntington disease (HD) involve multiple targets, including modulation of DNA repair and targeting the DNA mutation itself, RNA targeting of the huntingtin (HTT) gene, and disease-modifying therapies, according to presenter Jee Bang, MD, of Johns Hopkins Medicine, Baltimore, MD.
HD is a fatal progressive neurodegenerative disorder caused by the expansion of the glutamine-encoding cytosine, adenine, guanine (CAG) tract of the HTT gene. Somatic instability of mutant HTT in the brain can lead to further expansion of CAG in somatic cells, which is modulated by DNA damage-repair genes.
“CRISPR/Cas9 [a genome editing tool] shows benefit in large HD animal models,” Bang said. “Clinical trials continue to be very active in gene-based therapies, small molecules, and other targets including NMDA-receptor modulators, complement pathway, and vesicular monoamine transporter. Genome-wide association studies are now differentially associated with motor and cognitive symptoms and not just age of onset.”
One promising future therapy is Cas9-mediated replacement of expanded CAG repeats. In a pig model of HD, brain or intravenous injections of adeno-associated virus (AAV)-CRISPR/Cas9 reduced neurodegeneration and improved associated symptoms. CRISPR/Cas9 decreased mutant HTT to 50% or less, which was sufficient to reduce neuropathology and symptoms.
HTT-lowering strategies are a promising avenue for the development of disease-modifying therapies for HD, with antisense oligonucleotides being the first to reach clinical trials, including tominersen and WVE-003. The phase III pivotal GENERATION HD-1 study tested intrathecal tominersen at 120 mg every 8 weeks or 16 weeks against placebo. Target cerebrospinal fluid (CSF) and HTT-lowering was achieved in both drug groups. However, clinical efficacy was not demonstrated, with worsening of symptoms in the most frequently dosed group.
There was a trend toward improvement in the subgroup of younger patients with earlier stage disease. The phase II GENERATION HD-2 study will use a lower dose of tominersen with less frequent administration, and will include younger and earlier stage patients.
The phase 1b/2a SELECT-HD study of WVE-003 in Australia, Canada and Europe is allele-sensitive and includes patients with confirmed HD diagnosis with the SNP3 variant. Reductions in mean CSF mutant HTT and preservation of wild-type HTT have been observed in pooled analysis of single-dose cohorts.
Another therapeutic target is RNA interference using microRNA targeting huntingtin mRNA delivered as an intrastriatal injection. A phase I/II trial is comparing low and high doses of the recombinant AMT-130 versus sham surgery. At 12 months, results show a 53.8% reduction in CSF mutant HTT with CSF neurofilament light, a recognized biomarker of subcortical large-caliber axonal degeneration, near baseline.
Gene-based therapies are exciting, but small molecules are steadily developing as well, she said. One small molecule under investigation in HD is SAGE-718, an oxysterol-based NMDA-receptor modulator. NMDA-receptor decrease may contribute to cognitive dysfunction in HD.
Complement pathway in HD leads to neuronal stress and may induce aberrant activation of C1q. C1q dysfunction drives inappropriate synapse damage and loss, and may lead to significant cognitive impairment in HD. ANX005 is a humanized immunoglobulin G4 recombinant antibody against C1q that inhibits its function as the initiating molecule of the classical complement cascade.
An open-label, phase II trial of ANX005 shows reduced downstream complement and neuroinflammation and improved clinical function in patients with HD. The effect was greater in patients with higher baseline complement. A phase II/III blinded study in early manifest HD is expected this year, she said.
Valbenazine, a highly selective vesicular monoamine transporter 2 inhibitor, prevents dopamine uptake in HD. In the phase III KINECT-HD trial, valbenazine met the primary endpoint of significant improvement in chorea severity versus placebo, with improvements beginning in week 2. Clinically meaningful results were demonstrated by greater response rates seen by clinicians and patients for valbenazine. The open-label, rollover KINECT-HD2 study plans to enroll approximately 150 patients with HD to evaluate the long-term safety and tolerability of valbenazine.
References
Bang J. Updates in Huntington disease. Presented at the 75th Annual Meeting of the American Academy of Neurology, April 25, 2023.
Moss DJH, Pardiñas AF, Langbehn D, et al. Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study. Lancet Neurol 2017; 16(9):701-711. doi: 10.1016/S1474-4422(17)30161-8. Epub 2017 Jun 20. Erratum in: Lancet Neurol. 2017 Sep;16(9):683. PMID: 28642124.
Rook ME, Southwell AL. Antisense oligonucleotide therapy: From design to the Huntington disease clinic. BioDrugs 2022; 36(2):105-119. doi: 10.1007/s40259-022-00519-9.
Tabrizi SJ, Flower MD, Ross CA, et al. Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol 2020; 16(10):529-546. doi: 10.1038/s41582-020-0389-4.
Yan S, Zheng X, Lin Y, et al. Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington's disease. Nat Biomed Eng 2023 Feb 16. doi:10.1038/s41551-023-01007-3. Epub ahead of print.
Disclosures
Jee Bang, MD, has received personal compensation for serving as a consultant for GLG and Adept Field Solutions.