Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
624—Neurodegeneration: Protein Aggregation Disorders
Tuesday, November 12, 2013, 1:00 pm - 5:00 pm
624.05: Brain-targeted immunotherapy with single chain antibodies for synucleinopathies
Location: Halls B-H
*B. J. SPENCER1, S. EMADI2, S. MICHAEL3, K. KOSBERG3, E. ROCKENSTEIN3, A. ADAME3, M. SIERKS2, E. MASLIAH3; 1Neurotransit, San Diego, CA; 2Chem. Engin., Arizona State Univ., Tempe, AZ; 3Neurosciences, UCSD, San Diego, CA
Abstract Body: Parkinson’s disease, Dementia with Lewy bodies and Multiple Systems Atrophy are characterized by accumulation of α-synuclein (α-syn) in the CNS leading to neuronal dystrophy and death. Previous studies have shown that passive and active immunotherapy can reduce α-syn accumulation and associated deficits in animal models. However it is unclear if single chain antibodies (scfV) directed against α-syn oligomers might be also effective in animal models of synucleinopathies. For this purpose lentiviral vectors expressing a secreted (s) or a brain targeted (containing the apoB motif) anti-α-syn scFV that recognizes α-syn oligomers were generated and tested in an α-syn transgenic (tg) mouse model. The secreted form of the anti-α-syn oligomer scFV (D5 clone) was delivered by stereotaxic injections into the CNS. This resulted in reduced α-syn accumulation and improved neuronal pathology in the neocortex and hippocampus of α-syn tg mouse. The lenti-sD5 scFV containing the brain targeting peptide apoB was delivered by systemic injection into the α-syn tg. Analysis showed that the sD5-apoB was more effective than then sD5 scFv alone at crossing into the CNS and accumulated in neurons in the neocortex and hippocampus. In addition, the addition of the apoB peptide facilitated uptake and degradation of the α-syn/scFV complex by neuronal cells. The brain-targeted scFV was effective at reversing the neuro-pathology and memory deficits observed in the α-syn tg mouse model of DLB/PD. Thus the brain-targeted scFV may be an effective treatment for the accumulation of α-syn and may be a non-invasive therapy for treatment in humans.
Lay Language Summary: We have developed a brain-targeted antibody for the treatment of Parkinson’s Disease (PD). In a mouse model of PD, the antibody reduced the accumulation of the neuro-toxic -synuclein (-syn), improved neuronal health and increased learning and memory. In addition to these results, we showed a unique mechanism for the degradation of the -syn toxic protein. Over 1.5 million people in the US suffer from Parkinson’s disease and Dementia with Lewy Bodies and over 100,000 new cases are reported every year. To date, no treatments are currently available that will slow down the progression of these neurodegenerative disorders. Parkinson’s disease and DLB are characterized by the progressive degeneration of selective neurons associated with accumulation of -synuclein. -syn oligomers formed by progressive polymerization of -syn lead to neuronal loss and pathological symptoms associated with PD/DLB. Previous studies have shown that passive and active immunotherapy can reduce -syn accumulation and associated neuronal toxicity in animal models. However, clinical use of immunotherapy directed at neuronal degeneration has failed to result in effective therapeutics. This may be due to a lack of antibody transport to the brain or may be due to immune activation by full size antibodies. As an alternative to conventional antibody approaches, we have developed a single chain antibody (scFV) that is composed of only an antigen-binding domain and fused this with a brain targeting peptide. The scFV is directed against toxic oligomeric -syn without targeting normal -syn in the brain. The brain-targeting domain contains the LDL-receptor binding domain of apolipoprotein B allowing the targeted transport of the antibody across the blood-brain barrier for increased brain uptake. To test the hypothesis that the brain-targeted scFV would be effective against -syn in PD, we used a mouse model containing the human -syn gene. These mice accumulate -syn and have reduced neuronal connections as well as impairments in learning and memory (similar to patients with PD/ DLB). Delivery of the brain-targeted scFV by viral vector to the liver of the -syn mice resulted in significant accumulation of the scFV antibody in the brains of the mice. Subsequently we found significant reductions in accumulated -syn and -syn induced neuropathology compared to control treated mice. The mice that received the brain-targeted scFV showed improvements in learning and memory over the control non-targeted scFV treated mice. Importantly, we showed a unique mechanism for the import and degradation of the scFV--syn complexes in neurons. This pathway utilized receptors on the neuronal surface to recognize the brain-targeted scFV, import the scFV--syn complex and target for degradation. Unlike conventional treatments with monoclonal antibodies, this route of degradation does not result in immune cell activation that has been shown to cause pathogenic inflammation in the brain. Thus, the brain-targeted scFV designed against oligomeric -syn is effective at reducing pathogenic -syn by a unique degradation pathway and improving learning and memory in a mouse model of PD/DLB. This same approach may ultimately be useful for the treatment of Alzheimer’s disease, Huntington’s disease and other neurological diseases that are caused by accumulating toxic proteins.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit