Hilda Solanoy
A5043754873- Alzheimer's disease research and treatments
- Endoplasmic Reticulum Stress and Disease
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA regulation and disease
- Parkinson's Disease Mechanisms and Treatments
- Lysosomal Storage Disorders Research
- Cellular transport and secretion
- Genomics, phytochemicals, and oxidative stress
- Amyotrophic Lateral Sclerosis Research
- Plant Gene Expression Analysis
- Trypanosoma species research and implications
- Inflammation biomarkers and pathways
- Sirtuins and Resveratrol in Medicine
- Monoclonal and Polyclonal Antibodies Research
- Medicinal Plants and Bioactive Compounds
- Apelin-related biomedical research
- Drug Transport and Resistance Mechanisms
- Banana Cultivation and Research
- Cholinesterase and Neurodegenerative Diseases
- Bioactive natural compounds
- Histone Deacetylase Inhibitors Research
- RNA Interference and Gene Delivery
- Neuroscience and Neuropharmacology Research
- Epigenetics and DNA Methylation
- Glycogen Storage Diseases and Myoclonus
Denali Therapeutics (United States)
2019-2024
Genentech
2013
LRRK2 autophosphorylation on Ser 1292 may be a useful indicator of kinase activity, providing readout for screening candidate inhibitors.
Engineering human IgG1 Fc binding to a brain endothelial cell–enriched receptor allows enhanced exposure of biotherapeutics in multiple species.
Bispecific antibodies using the transferrin receptor (TfR) have shown promise for boosting antibody uptake in brain. Nevertheless, there are limited data on therapeutic properties including safety liabilities that will enable successful development of TfR-based therapeutics. We evaluate TfR/BACE1 bispecific variants mouse and show reducing TfR binding affinity improves not only brain but also peripheral exposure profile these antibodies. identify seek to address targeting with antibodies,...
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 activity is thought to impair lysosomal function and may contribute pathogenesis of PD. Thus, inhibition a potential disease-modifying therapeutic strategy DNL201 an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule inhibitor. In preclinical models, inhibited as evidenced by reduced phosphorylation both at serine-935...
An enzyme transport vehicle enables brain delivery of lysosomal enzymes across the blood-brain barrier in mice.
Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced...
Blocking dual leucine zipper kinase slows disease progression in animal models of ALS and Alzheimer’s disease.
Semorinemab shows beneficial effects in preclinical models and engages tau a phase 1 study of patients with Alzheimer’s disease.
Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression mutated transgenes have yielded key insights mechanisms disease, those are subject to artifacts, including random genetic integration transgene, ectopic expression and non-physiological protein levels. The engineering novel using knock-in approaches addresses some limitations. With...
Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse to platforms that bind transferrin receptor (TfR), brain endothelial cell target, facilitate receptor-mediated transcytosis BBB. Here, we characterized pharmacological behavior two distinct TfR-targeted fused iduronate 2-sulfatase (IDS), lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared relative exposures functional activities both mouse models. IDS...
Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report engineering and characterization a BBB transport vehicle targeting CD98 heavy chain (CD98hc or SLC3A2) heterodimeric amino acid transporters (TVCD98hc). The pharmacokinetic biodistribution properties CD98hc antibody (ATVCD98hc) are assessed in humanized knock-in mice cynomolgus monkeys. Compared to most existing platforms transferrin receptor, peripherally...
Dual leucine zipper kinase (DLK, MAP3K12) was recently identified as an essential regulator of neuronal degeneration in multiple contexts. Here we describe the generation potent and selective DLK inhibitors starting from a high-throughput screening hit. Using proposed hinge-binding interactions to infer binding mode specific design parameters optimize for CNS druglike molecules, came focus on di(pyridin-2-yl)amines because their combination desirable potency good brain penetration following...
The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although regulators and consequences PERK activation following neuronal injury are poorly understood. Here we show that signaling a component mouse MAP stress response controlled by Dual Leucine Zipper Kinase (DLK) contributes to DLK-mediated neurodegeneration. We find DLK-activating insults ranging from nerve neurotrophin deprivation result both c-Jun...
Abstract Variants in the leucine-rich repeat kinase 2 ( LRRK2 ) gene are associated with increased risk for familial and sporadic Parkinson’s disease (PD). Pathogenic variants LRRK2, including common variant G2019S, result activity, supporting therapeutic potential of inhibitors PD. To better understand role to support clinical development inhibitors, quantitative high-throughput assays measure levels activity needed. We developed applied such as well phosphorylation itself or one its...
Eukaryotic translation initiation factor 2B (eIF2B) is a key component of the integrated stress response (ISR), which regulates protein synthesis and granule formation in to cellular insult. Modulation ISR has been proposed as therapeutic strategy for treatment neurodegenerative diseases such vanishing white matter (VWM) disease amyotrophic lateral sclerosis (ALS) based on its ability improve homeostasis prevent neuronal degeneration. Herein, we report small-molecule discovery campaign that...
Recent data suggest that inhibition of dual leucine zipper kinase (DLK, MAP3K12) has therapeutic potential for treatment a number indications ranging from acute neuronal injury to chronic neurodegenerative disease. Thus, high demand exists selective small molecule DLK inhibitors with favorable drug-like properties and good CNS penetration. Herein we describe shape-based scaffold hopping approach convert pyrimidine 1 pyrazole core improved physicochemical properties. We also present the first...
Abstract Although the first generation of immunotherapies for Alzheimer’s disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem this class drugs. Here, we report an antibody transport vehicle (ATV) targeting transferrin receptor (TfR) brain delivery amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in mouse model deposition. Asymmetrical Fc mutations (ATV cisLALA )...
Background and Purpose The potential for therapeutic antibody treatment of neurological diseases is limited by poor penetration across the blood–brain barrier. I.c.v. delivery a promising route to brain; however, it unclear how efficiently antibodies delivered i.c.v. penetrate cerebrospinal spinal fluid (CSF)‐brain barrier distribute throughout brain parenchyma. Experimental Approach We evaluated pharmacokinetics pharmacodynamics an inhibitory monoclonal against β‐secretase 1 (anti‐BACE1)...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested inhibition epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed extend survival it did...
Dual leucine zipper kinase (DLK) and zipper-bearing (LZK) are regulators of neuronal degeneration axon growth. Therefore, there is a considerable interest in developing DLK/LZK inhibitors for neurodegenerative diseases. Herein, we use ligand- structure-based drug design approaches identifying novel amino-pyrazine DLK/LZK. DN-1289 (14), potent selective dual inhibitor, demonstrated excellent vivo plasma half-life across species anticipated to freely penetrate the central nervous system with...
The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that activated to multiple sources of cellular stress. Although acute activation this restores homeostasis, intense or prolonged ISR perturbs cell function and may contribute neurodegeneration. DNL343 an investigational CNS-penetrant small molecule inhibitor designed activate the initiation factor 2B (eIF2B) suppress aberrant activation. reduced CNS activity neurodegeneration dose-dependent manner two established...
Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation glycosaminoglycans (GAGs) throughout body. Treatment MPS remains considerable challenge as current enzyme replacement therapies do not adequately control many aspects disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that engineered to bind transferrin receptor; this...