Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints

Abstract

Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)mediated PrP suppression extends survival and delays disease onset in intracerebrally prioninfected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains, with no evidence for the development of drug resistance. We demonstrate that less than 25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Both neuroinflammation measured through live animal bioluminescence imaging and neuronal injury measured by plasma neurofilament light chain can be reversed by a single dose of PrPlowering ASO administered after the detection of pathological change in these biomarkers. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. Taken together, these results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

Genome-wide transcriptomics identifies an early preclinical signature of prion infection

“…And yet the plasma experiment suggests that treatment aimed at rescuing the molecular alterations identified in the clinically silent phase might impact the consequent entire progression of the disease. This idea is also in line with emerging results of novel potential therapies which seem to be effective only when started either prophylactically or within the first 11 weeks after prion inoculation [30]. The fact that young plasma seems to improve the health span, rather than the lifespan, of prion disease may be relevant to improving the life quality of patients with neurodegenerative diseases.…”

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

“…The well-defined pathobiology of prion disease, with prion protein (PrP) as the sole causal agent [1], has spurred preclinical development of PrP-lowering drugs [2,3]. The rapid progression of prion disease, which is typically fatal in under a year [4], presents a challenge for drug development, as symptomatic patients may be profoundly debilitated by the time of diagnosis and enrollment [5,6].…”

Multimodal small-molecule screening for human prion protein binders

“…No effective therapeutics currently exist for prion disease, but PrP is a genetically and pharmacologically validated drug target 2 . PrPlowering antisense oligonucleotides (ASOs) are in preclinical development [3][4][5] , and PrP-binding antibodies have been tested preclinically 6 as well as clinically in a compassionate use context 7 . Here, we sought to augment the therapeutic pipeline by discovering small molecules that bind PrP.…”