Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme

Mead, Simon; Khalili-Shirazi, Azadeh; Potter, Caroline; Mok, Tzehow; Nihat, Akin; Hyare, Harpreet; Canning, Stephanie; Schmidt, Christian; Campbell, Tracy; Darwent, Lee; Muirhead, N.; Ebsworth, Nicolette M.; Hextall, Patrick; Wakeling, Madeleine; Linehan, Jacqueline M.; Libri, Vincenzo; Williams, Bryan; Jaunmuktane, Zane; Brandner, Sebastian; Rudge, Peter; Collinge, John

doi:10.1016/s1474-4422(22)00082-5

Cited by 66 publications

(37 citation statements)

References 35 publications

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“…PRN100, a monoclonal antibody treatment recently offered to a small number of patients with sCJD, exemplifies one such innovative opportunity which relies on early patient diagnoses. Other experimental compounds are also being developed [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Assessing initial MRI reports for suspected CJD patients

et al. 2022

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Background MRI is invaluable for the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), demonstrating characteristic diffusion abnormalities. Previous work showed these changes were often not reported (low sensitivity), leading to eventual diagnosis at a more advanced state. Here, we reviewed the situation a decade later, on the presumption of improved access and awareness over time. Methods We reviewed initial MRI scans of 102 consecutive suspected sCJD patients recruited to the National Prion Monitoring Cohort study between 2015 and 2019, assessing for characteristic signal changes in the striatum, thalamus and cortical ribbon. We compared our findings to formal reports from referring centres. Requesting indications were studied to assess if they were suggestive of CJD. Patients were examined and their MRC Prion Disease Rating Scale scores recorded. Results We identified characteristic MRI abnormalities in 101 cases (99% sensitivity), whilst referring centres reported changes in 70 cases (69% sensitivity), which was a significant improvement in reporting sensitivity from 2012. Reporting sensitivity was associated with signal change in the cerebral cortex, and with the number of regions involved, but not significantly affected by clinical information on request forms, or referring centres being regional neuroscience/non-neuroscience centres. Similar to a previous study, patients with missed abnormalities on initial reporting possessed lower MRC Scale scores when referred to the NPC than those correctly identified. Conclusions Whilst local MRI reporting of sCJD has improved with time, characteristic abnormalities remain significantly under detected on initial scans. Sensitivity is better when the cerebral cortex and multiple regions are involved. We re-emphasize the utility of MRI and encourage further efforts to improve awareness and sensitivity in the assessment of patients with rapidly progressive dementia.

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Section: Introductionmentioning

confidence: 99%

Assessing initial MRI reports for suspected CJD patients

et al. 2022

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“…In part, this relates to the rarity of the disease and the challenges evident from rapid progression. Two experimental treatments have currently either entered human use, or are planned for human use: monoclonal antibody therapy 29 and antisense oligonucleotide treatments. The mechanism of actions may require time for the compound to achieve target therapeutic levels in brain tissues, and clinical trials may be less powerful if patients are recruited with a very short prognosis.…”

Section: Discussionmentioning

confidence: 99%

Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

Nihat

Ranson

Harris

et al. 2022

Brain Communications

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Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. 537 patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100- day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. 280 (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for MM compared to MV polymorphism; 95% CI 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care.

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“…α-helix 1 in particular has been implicated in the conversion to PrP Sc (56, 57), with the anti-PrP therapeutic monoclonal antibody ICSM18 effectively curing prion-infected cells through binding to and stabilising α-helix 1 of PrP C (58). Indeed its humanised version has been used in the first-in-human treatment programme using an anti-PrP C monoclonal antibody (59).…”

Section: Discussionmentioning

confidence: 99%

Loss of the first β-strand of human prion protein generates an aggregation-competent partially “open” form

Hosszu

Sangar

Batchelor

et al. 2022

Preprint

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Prion diseases, a group of incurable, lethal neurodegenerative disorders of mammals including humans, are caused by prions, assemblies of misfolded host prion protein (PrP). The pathway of PrP misfolding is still unclear, though previous data indicate the presence of a structural core in cellular PrP (PrPC), whose cooperative unfolding presents a substantial energy barrier on the path to prion formation. PrP is a GPI-anchored membrane protein, and a number of studies suggest that membrane interactions play an important role in the conversion of PrPC to its disease-associated form, including a transmembrane form of PrP in which a highly conserved region (residues 110 - 136) spans the ER membrane. Insertion of this region results in the detachment of the PrPC first β-strand from the structural core. The effect of this removal on the structure, stability and self-association of the folded domain of PrPC is determined here through a biophysical characterisation of a truncated form of PrPC lacking this region. Whilst markedly destabilised, NMR chemical shifts show that the truncated protein exhibits tertiary structure characteristic of a fully folded protein and retains its native secondary structure elements, including the second strand of the PrP β-sheet, but with altered conformational flexibility in the β2-α2 loop and first α-helix. The latter is destabilised relative to the other helical regions of the protein, with markedly increased solvent exposure. This truncated form of PrP fibrilises more readily than the native form of the protein. These data suggest a stepwise mechanism, in which a destabilised "open" form of PrPC may be a key intermediate in the refolding to the fibrillar, pathogenic form of the protein.

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Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme

Cited by 66 publications

References 35 publications

Assessing initial MRI reports for suspected CJD patients

Assessing initial MRI reports for suspected CJD patients

Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

Loss of the first β-strand of human prion protein generates an aggregation-competent partially “open” form

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