Towards a treatment for genetic prion disease: trials and biomarkers

Vallabh, Sonia M; Minikel, Eric Vallabh; Schreiber, Stuart L.; Lander, Eric S.

doi:10.1016/s1474-4422(19)30403-x

Cited by 63 publications

(65 citation statements)

References 84 publications

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“…PrP-lowering therapeutics are now in preclinical development, so CSF PrP will be important as a pharmacodynamic biomarker at a minimum, and regulators have expressed openness to its use as a surrogate endpoint in pre-symptomatic individuals [10]. Productive use of this marker in trials, however, will require dependable performance, including a stable baseline, which might not exist if CSF PrP exhibits high biotemporal variability or if pre-symptomatic individuals exhibit a decline in CSF PrP, similar to the lowered CSF PrP levels seen in symptomatic prion disease patients [25,47,48].…”

Section: Discussionmentioning

confidence: 99%

“…Individuals with mutations in the prion protein (PRNP) gene, many of which are highly penetrant [7], may be aware of their risk decades in advance of symptom onset [8], creating an opportunity for early intervention. However, because the unpredictable age of onset precludes randomizing pre-symptomatic individuals to a disease onset endpoint [9], pre-symptomatic trials may instead need to rely on a surrogate biomarker endpoint [10].…”

Section: Introductionmentioning

confidence: 99%

“…"Primary prevention" trials might recruit presymptomatic individuals at known high genetic risk without requirement of prodromal pathology and treat toward a pharmacodynamic biomarker deemed reasonably likely to predict clinical benefit: CSF PrP levels [10].…”

Section: Introductionmentioning

confidence: 99%

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

Vallabh

Minikel

Williams

et al. 2020

BMC Med

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Background: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. Methods: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. Results: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Vallabh

Minikel

Williams

et al. 2020

BMC Med

Self Cite

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“…Prion disease, a rapidly fatal and currently untreatable neurodegenerative disease, is caused by the post-translational conformational corruption of host-encoded prion protein (PrP) 1 . Due to its central role in disease pathophysiology, reduction of native PrP is an attractive therapeutic hypothesis in prion disease 2 . Homozygous deletion of PrP prevents prion infection 3,4 , while heterozygous PrP knockout delays development of disease following prion infection [4][5][6][7] and transgenic PrP overexpression accelerates it 8 , providing genetic evidence of a continuous doseresponse relationship between PrP dosage and disease susceptibility.…”

Section: Introductionmentioning

confidence: 99%

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

Minikel

Zhao

et al. 2020

Preprint

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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.

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“…Due to its low prevalence and lack of prodromal markers, clinical phase III trials involving several hundred symptomatic individuals are not feasible in human prion disease. Current efforts are focused on presymptomatic trials in genetic prion disease individuals which might lead to adequately powered trials [46].…”

Section: Suppression Of Prion Protein Gene Expressionmentioning

confidence: 99%

Recent developments in antibody therapeutics against prion disease

Frontzek

Aguzzi

2020

Emerging Topics in Life Sciences

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Preclinical evidence indicates that prion diseases can respond favorably to passive immunotherapy. However, certain antibodies to the cellular prion protein PrPC can be toxic. Comprehensive studies of structure–function relationships have revealed that the flexible amino-terminal tail of PrPC is instrumental for mediating prion toxicity. In a first-in-human study, an anti-prion antibody has been recently administered to patients diagnosed with sporadic Creutzfeldt–Jakob's disease, the most prevalent human prion disease. Moreover, large-scale serosurveys have mapped the prevalence of naturally occurring human anti-prion autoantibodies in health and disease. Here, we provide a perspective on the limitations and opportunities of therapeutic anti-prion antibodies.

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Towards a treatment for genetic prion disease: trials and biomarkers

Cited by 63 publications

References 84 publications

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

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

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

Recent developments in antibody therapeutics against prion disease

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