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Bonner, J. M.

Publications and source records attributed to Bonner, J. M..

2 recordsLinked to original sources
bioRxiv2024

A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies

Parkinsons disease and multiple system atrophy are members of a class of devastating neurodegenerative diseases called synucleinopathies, which are characterized by the presence of alpha-synuclein (-Syn) rich aggregates in the brains of patients. Passive immunotherapy targeting these aggregates is an attractive disease-modifying strategy. Such an approach must not only demonstrate target selectivity towards -Syn aggregates, but also achieve appropriate brain exposure to have the desired therapeutic effect. Here we present preclinical data for a next-generation antibody for the treatment of synucleinopathies. SAR446159 (ABL301) is a bispecific antibody composed of an -Syn-binding immunoglobulin (IgG) and an engineered insulin-like growth factor receptor 1 (IGF1R) binding single-chain variable fragment (scFv), acting as a shuttle to transport an antibody across the blood-brain barrier (BBB). SAR446159 binds tightly and preferentially to -Syn aggregates and prevents their seeding capacity in vitro and in vivo. Incubation with SAR446159 reduced -Syn preformed fibrils (PFFs) uptake in neurons and facilitated uptake and clearance by microglia. In wild type mice injected in the striatum with -Syn PFFs, treatment with SAR446159 reduced the spread of aSyn pathology as measured by phosphorylated -Syn staining and lessened the severity of motor phenotypes. Additionally, in 9-month-old transgenic mice overexpressing -Syn (mThy1--Syn, Line 61), repeated treatment with SAR446159 reduced markers of -Syn aggregation in the brain. SAR446159 had significantly higher brain and CSF penetration over a sustained period than its monospecific counterpart (1E4) in rats and monkeys. The binding properties of SAR446159 combined with its brain-shuttle technology make it a potent, next-generation immunotherapeutic for treating synucleinopathies.

neuroscience↗
bioRxiv2023

A single-cell atlas of ABCA7 loss-of-function reveals lipid disruptions, mitochondrial dysfunction and DNA damage in neurons

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimers disease risk (odds ratio {approx} 2), yet the underlying pathogenic mechanisms and specific neural cell types affected remain unclear. To investigate this, we generated a single-nucleus RNA sequencing atlas of 36 human postmortem prefrontal cortex samples, including 12 carriers of ABCA7 LoF variants and 24 matched non-carriers. ABCA7 LoF variants were associated with transcriptional changes across all major neural cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed significant alterations in oxidative phosphorylation, lipid metabolism, DNA damage responses, and synaptic signaling pathways. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers) predicted by molecular dynamic simulations to disrupt ABCA7 structure -, indicating that findings from our study may extend to large portions of the at-risk population. Human induced pluripotent stem cell (iPSC)-derived neurons carrying ABCA7 LoF variants closely recapitulated the transcriptional changes observed in human postmortem neurons. Biochemical experiments further demonstrated that ABCA7 LoF disrupts mitochondrial membrane potential via regulated uncoupling, increases oxidative stress, and alters phospholipid homeostasis in neurons, notably elevating saturated phosphatidylcholine levels. Supplementation with CDP-choline to enhance de novo phosphatidylcholine synthesis effectively reversed these transcriptional changes, restored mitochondrial uncoupling, and reduced oxidative stress. Additionally, CDP-choline normalized amyloid-{beta} secretion and alleviated neuronal hyperexcitability in ABCA7 LoF neurons. This study provides a detailed transcriptomic profile of ABCA7 LoF-induced changes and highlights phosphatidylcholine metabolism as a key driver in ABCA7-induced risk. Our findings suggest a promising therapeutic approach that may benefit a large proportion of individuals at increased risk for Alzheimers disease.

neuroscience↗