Progressive Multifocal Leucoencephalopathy (PML)
Progressive multifocal leukoencephalopathy (PML) is a rare but debilitating and frequently fatal viral disease of the central nervous system, primarily affecting individuals with chronically and severely suppressed immune systems. PML is a serious demyelinating disease of the brain, often resulting in severe disability or death, caused by lytic infection of oligodendrocytes by the JC polyomavirus (JCV). The disease was relatively obscure until the outbreak of HIV/AIDS, when it presented as one of the more frequent opportunistic infections in this immune deficiency syndrome. It attracted additional attention from the medical and scientific community following the discovery of significant PML risk associated with natalizumab, a monoclonal antibody used for treatment of relapsing-remitting multiple sclerosis. This was followed by association of PML with other immunosuppressive or immunomodulating drugs. PML is currently an untreatable disease with poor outcomes, so it is a significant concern when developing new immunotherapies. Current prophylaxis and treatment of PML are focused on immune reconstitution, restoration of immune responses to JC virus infection, and eventual suppression of immune reconstitution inflammatory syndrome. This approach was successful in reducing the incidence of PML and improved survival of PML patients with HIV infection. However, the outcome for the majority of PML patients, regardless of their medical history, is still relatively poor. There is a high unmet need for both prophylaxis and treatment of PML (according to Pavlovic et al., Ther Adv Neurol Disord 2015, Vol. 8(6) 255 –273).
Use of NEUWAY´s empty EPCs as potential vaccine to treat or prevent PML
NEUWAY´s EPCs are derived from the capsid protein VP1 of the human John Cunningham virus (JCV). They are composed of 72 pentamers of VP1. The capsule closely resembles the outer surface of the JC virus. Hence, it was reasoned that the empty capsule (IMP Code: NWP007) could be effectively used as a therapeutic vaccine against JCV if administered subcutaneously together with an adjuvant.
Clinical Experience with NEUWAY ´s compound NWP007 on a named patient basis
Positive results of immunization with NWP007 vaccine in combination with an immune stimulus and adjuvant was demonstrated in 3 patients.
Sospedra et al (2014) showed that vaccination of two PML patients with NWP007 resulted in an increase in neutralizing titer of antibodies against both wild-type and PML mutant JCV. This correlated with resolution of PML progression as determined by brain MRI, induction of robust JCV VP-1 specific CD4 T cell proliferation, substantial reductions in JCV DNA viral load in CSF, and clinical improvement with slight delay after developing a JCV-specific immune response
Ray et al. (2015) observed similar improvements in one PML patient with idiopathic CD4 lymphopenia. Vaccination with NWP007 was followed by a roughly 100-fold increase in the patient’s neutralizing titer against her cognate mutant virus. After vaccination, the patient showed an extraordinarily high peak titer (25 million) against her inferred wild type JCV. In parallel there were substantial reductions in JCV DNA viral load in CSF and plasma detected.
- Pavlovic, D., Patera A.C., Nyberg F. et al. (2015) Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Therapeutic Advances in Neurological Disorders 8: 255-73.
- Ray U, Cinque P, Gerevini S et al. (2015) JC Polyomavirus Mutants Escape Antibody-Mediated Neutralization. Science Translational Medicine 7 (306): 306ra151 + supplementary materials.
- Sospedra M, Schippling AS, Yousef S et al. (2014) Treating progressive multifocal leukoencephalopathy with Interleukin 7 and vaccination with JC virus capsid protein VP1. Clinical Infectious Diseases 59(11):1588-92 + supplementary materials.
- PML Consortium - http://pmlconsortium.org