A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models.

Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.

Patient satisfaction and cost savings analysis of the telemedicine program within a neuro-oncology department.

PURPOSE: Unique challenges exist in the utilization of telemedicine for neurological and surgical specialties. We examined the differences in patient satisfaction for telemedicine versus in-person visits within a Neuro-Oncology Program to assess whether there was a difference between surgical and medical specialties. We also examined the potential cost savings benefits of utilizing telemedicine. METHODS: 1189 Press Ganey surveys in the Department of Neuro-Oncology (982 in-person and 207 telemedicine) by surgical and medical neuro-oncology patients between 04/01/2020 and 06/30/2021 were reviewed. Survey results were divided into 4 categories (Access, Provider, Technology (telemedicine only), and Overall Satisfaction). Results were analyzed for the impact of telemedicine versus in-person visits, and gender, age, insurance, and specialty. Cost savings were calculated based on potential travel distance and lost productivity. RESULTS: Survey results from telemedicine visits demonstrated that patients with private insurance returned higher scores in the Provider (p = 0.0089), Technology (p = 0.00187), and Overall (p = 0.00382) categories. Surgical patients returned higher scores for Access (p = 0.0015), Technology (p = 0.0002), and Overall (p = 0.0019). When comparing telemedicine to in-person scores, in-person scored higher in Provider (p = 0.0092) for all patients, while in-person scored higher in Access (p = 0.0252) amongst surgical patients. Cost analysis revealed that telemedicine allowed patients to save an average of 4.1 to 5.6 h per visit time and a potential cost savings of up to $223.3 ± 171.4. CONCLUSION: Telemedicine yields equivalent patient satisfaction when employed in surgical as compared to medical Neuro-Oncology patients with the potential to lessen the financial and time burden on neuro-oncology patients.

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region.

Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid ß-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state.