Periodic Reporting for period 1 - NeuroQure (Neuroprotective human antibodies to the flexible tail of the prion protein)
Berichtszeitraum: 2017-09-01 bis 2019-02-28
Genetic prion diseases are heritable and as yet incurable diseases of the central nervous system caused by mutations of the prion protein gene PRNP. Although carriers of PRNP variants are exposed to the mutation their whole life, they often develop clinically manifest disease only at an advanced age. This is indicative of protective factors, which may consist, at least in part, of anti-prion autoantibodies, i.e. antibodies against a “self“-protein. Isolation of therapeutic autoantibodies from healthy mutation carriers could pave the way to an effective and tolerable therapy against prion disease.
We have retrospectively assessed autoantibody reactivity in blood from individuals encompassing a wide spectrum of PRNP variants. In a collaborative effort, we have recruited 103 mutation carriers from Austria, Canada, France, Germany, Italy, Slovakia, Spain, Switzerland and the United States of America. Unaffected family members from mutation carriers (68 patients) and patients suffering from brain diseases other than prion disease (50 patients) were used as controls. We also included patients diagnosed with other, non-heritable prion diseases such as variant Creutzfeldt-Jakob’s disease (4 patients) and sporadic Creutzfeldt’s Jakob disease (35 patients). We found that autoantibody levels did not differ between clinically manifest or silent genetic prion disease patients. Similarly, autoantibody levels in genetic prion disease patients did not differ when compared to unaffected family members from PRNP mutation carriers or patients diagnosed with brain diseases other than prion disease. Interestingly, when we compared patients with clinical signs of any prion disease to all other individuals, autoantibodies against the prion protein were strongly correlated with prion disease symptoms. We conclude that pathogenic PRNP variants do not notably stimulate antibody-mediated immunity. It will be important, however, to investigate autoantibodies against the prion protein in clinically silent individuals as they may represent a unique repertoire of naturally occurring, therapeutic autoantibodies.
We have also tested 48,708 samples from an unselected patient cohort for the presence of autoantibodies against the cellular prion protein (PrPc). We identified 34 patients (0.07% of the tested cohort) with detectable and distinct anti-PrPC reactivity. Preliminary data do not suggest a correlation between anti-PrPC-autoantibody titres and specific diseases, while the final analyses are currently ongoing.
Having identified patients harbouring putative anti-PrP antibodies, the cloning of antibodies from these individuals has become a major focus. As the isolation of PrP-reactive memory B cells from the surplus cellular material of patients has proven enormously difficult, we have sought to obtain and received the ethical permit to re-contact patients who signed the hospital-wide general consent and to ask them for a second blood donation. So far, two individuals with a clearly distinct plasma reactivity donated their blood and entered the cloning process at Mabylon AG. However, no functional anti-PrP IgG has been derived so far. While we strongly pursue the development of antibodies directed against the prion protein, it is clear that the availability of human-derived monoclonal anti-PrP-autoantibodies may greatly influence the scientific understanding of neurodegenerative diseases and may enable prion immunotherapy. The joint efforts between the Institute of Neuropathology and Mabylon AG are continuing.
We have retrospectively assessed autoantibody reactivity in blood from individuals encompassing a wide spectrum of PRNP variants. In a collaborative effort, we have recruited 103 mutation carriers from Austria, Canada, France, Germany, Italy, Slovakia, Spain, Switzerland and the United States of America. Unaffected family members from mutation carriers (68 patients) and patients suffering from brain diseases other than prion disease (50 patients) were used as controls. We also included patients diagnosed with other, non-heritable prion diseases such as variant Creutzfeldt-Jakob’s disease (4 patients) and sporadic Creutzfeldt’s Jakob disease (35 patients). We found that autoantibody levels did not differ between clinically manifest or silent genetic prion disease patients. Similarly, autoantibody levels in genetic prion disease patients did not differ when compared to unaffected family members from PRNP mutation carriers or patients diagnosed with brain diseases other than prion disease. Interestingly, when we compared patients with clinical signs of any prion disease to all other individuals, autoantibodies against the prion protein were strongly correlated with prion disease symptoms. We conclude that pathogenic PRNP variants do not notably stimulate antibody-mediated immunity. It will be important, however, to investigate autoantibodies against the prion protein in clinically silent individuals as they may represent a unique repertoire of naturally occurring, therapeutic autoantibodies.
We have also tested 48,708 samples from an unselected patient cohort for the presence of autoantibodies against the cellular prion protein (PrPc). We identified 34 patients (0.07% of the tested cohort) with detectable and distinct anti-PrPC reactivity. Preliminary data do not suggest a correlation between anti-PrPC-autoantibody titres and specific diseases, while the final analyses are currently ongoing.
Having identified patients harbouring putative anti-PrP antibodies, the cloning of antibodies from these individuals has become a major focus. As the isolation of PrP-reactive memory B cells from the surplus cellular material of patients has proven enormously difficult, we have sought to obtain and received the ethical permit to re-contact patients who signed the hospital-wide general consent and to ask them for a second blood donation. So far, two individuals with a clearly distinct plasma reactivity donated their blood and entered the cloning process at Mabylon AG. However, no functional anti-PrP IgG has been derived so far. While we strongly pursue the development of antibodies directed against the prion protein, it is clear that the availability of human-derived monoclonal anti-PrP-autoantibodies may greatly influence the scientific understanding of neurodegenerative diseases and may enable prion immunotherapy. The joint efforts between the Institute of Neuropathology and Mabylon AG are continuing.