By Isabella Colonna
For May we have selectedMead S, Khalili-Shirazi A, Potter C, Mok T, Nihat A, Hyare H, Canning S, Schmidt C, Campbell T, Darwent L, Muirhead N, Ebsworth N, Hextall P, Wakeling M, Linehan J, Libri V, Williams B, Jaunmuktane Z, Brandner S, Rudge P, Collinge J. Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt-Jakob disease: evaluation of a first-in-human treatment programme. Lancet Neurol. 2022 Apr;21(4):342-354. doi: 10.1016/S1474-4422(22)00082-5. PMID: 35305340.
Prion diseases are rapidly progressive neurodegenerative conditions which can affect both humans and animals, leading to death a few months after the onset of symptoms. The commonest prion disease in humans is Creutzfeldt-Jakob disease (CJD), with an incidence of 1-2 cases per million people. Currently, no effective therapies are available.
This study, conducted in the UK, evaluated an experimental treatment for human prion disease, based on a fully humanised monoclonal antibody (PRN100) addressed against the cellular prion protein (PrP). Six patients with a clinical diagnosis of probable CJD were enrolled in this study and underwent blood tests, MRI imaging, CSF analysis, as well as neurophysiological examinations at the baseline and approximately every 6 weeks. The treatment with PRN100 was administered by a 4-hour intravenous infusion; initial dose was 1 mg/kg, which was gradually increased up to 80 mg/kg. The dosage of 80 mg/kg was repeated every two weeks until the patient’s death or withdrawal. PRN100 concentrations were assessed both in serum and CSF after its administration. Post-mortem neuropathological examinations were performed in two patients only. Clinical scores and survival of treated patients were compared with clinical data of untreated CJD individuals from the National Prion Monitoring Cohort study.
This study showed that PRN100 was safe and able to cross the blood-brain barrier in target concentrations after intravenous administration. Target concentrations in CSF were identified at 50 nM, as described in previous preclinical studies. Despite the treatment, all patients presented a rapidly progressive neurological decline. However, it is noteworthy to mention that all study participants were at the mid-stages of the disease at the beginning of the treatment; moreover, because of the cautious dose-escalation protocol, it took a mean of 47 days to reach the CSF target concentrations. Further, post-mortem neuropathological investigations were performed in two patients only, aiming to evaluate if there were alterations in the brain microstructure after treatment. The authors detected tissue-bound PRN100 IgG in multiple brain regions and did not find any signs of neurotoxicity.
These encouraging findings identify PRN100 as a potential therapeutic option for CJD. Moreover, PRN100 might become particularly promising as secondary prophylaxis in asymptomatic individuals known to be infected by prions or to be carriers of pathogenic PRNP mutations. Formal efficacy trials are now warranted in order to evaluate treatment with PRN100 in a larger cohort of patients at early clinical stages.