Biology subjects

Lewis, M. M.

Publications and source records attributed to Lewis, M. M..

5 recordsLinked to original sources

bioRxiv2023

Electrostatic-driven Interactions Enhance Intratumoral Retention and Antitumor Efficacy of Immune Checkpoint Blockade Antibodies

Tumor extracellular matrix (ECM) forms a net negative charged network that interacts with and hinders the transport of molecules partly based on electrostatic interactions. The focus on drug delivery in solid tumors has traditionally been on developing neutral charge coatings to minimize interactions with the ECM for improved transport. In contrast to this prior work, we recently found a cationic peptide that interacted electrostatically with the negatively charged components of the ECM, resulting in enhanced uptake and retention of nanoparticles in tumor ECM and tumor tissue. Based on this previous study, here, we hypothesize that the electrostatically driven interactions of the cationic peptide will improve the binding and retention of immune checkpoint blockade antibodies (ICBs), ultimately enhancing their antitumor immunogenic responses. We prepared peptide antibody (Ab) conjugates by conjugating the cationic peptide to ICBs, anti-cytotoxic T lymphocyte antigen 4 ({propto}-CTLA4) and anti-programmed cell death ligand-1 ({propto}-PD-L1) Abs, using copper-free click chemistry. We confirmed an average of 1 - 2 peptides per Ab. The cationic peptide electrostatically interacted with the net negatively charged tumor ECM and improved the binding of the Abs to the tumor ECM without affecting their antigen recognition capacities. Modifying the Abs due to cationic peptide conjugation reduced the systemic exposure of the Abs and did not induce treatment-related toxicities. We quantified a significantly higher population of tumor-infiltrating CD8+ T cells and a significant depletion of regulatory T cells in the tumor and tumor-draining lymph nodes upon peptide conjugation, which resulted in a better therapeutic outcome of the ICBs. ONE SENTENCE SUMMARYElectrostatic interaction-based intratumoral retention enhances antitumor responses of immune checkpoint blockade antibodies upon local administration.

bioengineering↗

bioRxiv2023

Applying machine learning to identify ionizable lipids for nanoparticle-mediated delivery of mRNA

mRNA lipid nanoparticles (LNPs) have a tremendous potential to treat, cure, or prevent many diseases. To identify promising candidates for each application, most studies screen dozens to hundreds of formulations with ionizable lipids synthesized using a single type of chemistry. However, this technique leaves the ionizable lipids synthesized through multi-step chemistries underexplored. This gap in the repertoire of structures is of particular significance because it affects the screening of analogs that are structurally similar to SM-102 and ALC-0315, the ionizable lipids used to formulate the clinically approved mRNA LNP COVID-19 vaccines. Herein, we address this by employing LightGBM, a machine learning algorithm, to reduce the burden of screening these types of ionizable lipids by learning from the breadth and diversity of lipids that have already been tested. We first evaluate the ability of LightGBM to predict LNP potency across heterogeneous chemistries from different studies to achieve an R2 of 0.94. After establishing the predictive capacity of the model, we then identify the number of outside carbons in the ionizable lipid as the most important factor contributing to transfection efficiency. From this finding, we subsequently apply the algorithm to predict the effect of formulating nanoluciferase mRNA LNPs using analogs of SM-102 and ALC-0315 with small changes in the number of outside carbons on luciferase activity in HEK293T cells and achieve an R2 of 0.83. Importantly, this correlation encompasses novel lipids not included within the database used to train the algorithm. Overall, this study demonstrates the potential of machine learning to accelerate the development of new ionizable lipids by simplifying the screening process.

bioengineering↗

bioRxiv2023

Discovery of peptides for targeted delivery of mRNA lipid nanoparticles to cystic fibrosis lung epithelia

For cystic fibrosis (CF) patients, a lung targeted gene therapy would significantly alleviate pulmonary complications associated with morbidity and mortality. However, mucus in the airways and cell entry pose huge delivery barriers for local gene therapy. Here, we used phage display technology to select for and identify mucus- and cell-penetrating peptides against primary human bronchial epithelial cells (pHBECs) from CF patients cultured at air-liquid interface (ALI). At ALI, pHBECs produce mucus and reflect CF disease pathology, making it a clinically relevant model. Using this model, we discovered a lead candidate peptide, and incorporated it into lipid nanoparticles (LNPs) to deliver mRNA to pHBECs and mouse lungs in vivo. Compared to LNPs without our peptide, peptide-LNPs demonstrated 7.8-fold and 4.8-fold higher mRNA expression in vitro and in vivo, respectively. Since gene delivery to pHBECs is a significant challenge, we are encouraged by these results and anticipate that our peptide could be used to successfully deliver CF gene therapies in future work.

bioengineering↗

bioRxiv2021

IMPAIRED OLFACTORY NETWORK FUNCTIONAL CONNECTIVITY IN PARKINSON'S DISEASE: A NOVEL MARKER FOR DISEASE PROGRESSION

ObjectiveDetermine the neural basis of olfactory impairment in akinetic-rigid (PDAR) and tremor predominant (PDT) Parkinsons disease subtypes. MethodsWe combined resting-state fMRI (rs-fMRI) with seed based functional connectivity (FC) in order to delineate the olfactory networks functional connectivity (ON FC) between PDAR and PDT patients. We then contrasted their ON FC patterns with cognitively normal (CN) subjects. All three groups were closely matched in age, demographic variables, and adjusted for relative cognitive performance. Olfactory function was measured using the University of Pennsylvania Smell Identification Test (UPSIT). ResultsUPSIT scores were lower in akinetic-rigid vs tremor subtypes; ON FC values were lower in PDAR compared to PDT and CN, and followed the trend observed in UPSIT scores. UPSIT scores and ON FC values were significantly correlated, reflecting the effects of PD pathologies. ConclusionsThe results show that olfactory function differs between PDAR and PDT suggesting a correlation between PD-related motor symptoms and olfactory deficits. ON FC differences accounts for the impaired olfactory functions observed between PDAR and PDT. PDAR is known to have worse clinical outcomes and faster cognitive decline compared to PDT; therefore, PD-related olfactory dysfunction may serve as a novel metric for enhancing PD prognosis.

neuroscience↗

bioRxiv2021

Decoupling of global brain activity and cerebrospinal fluid flow in Parkinson's cognitive decline

BackgroundDeposition and spreading of misfolded proteins (-synuclein and tau) have been linked to Parkinsons cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow that may reflect glymphatic function. ObjectiveTo determine if the decoupling of brain activity-CSF flow is linked to Parkinsons cognitive dysfunction. MethodsFunctional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment, MoCA) scores were collected from 60 Parkinsons and 58 control subjects. Parkinsons patients were subgrouped into those with (MoCA < 26; N = 29) and without (MoCA [≥] 26; N = 31) mild cognitive impairment (MCI). The coupling strength between the resting-state global blood-oxygen-level-dependent signal (gBOLD) and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. ResultsgBOLD-CSF coupling decreased significantly (p < 0.006) in Parkinsons patients showing MCI, compared to those without MCI and controls. Reduced gBOLD-CSF coupling was associated with decreased MoCA scores that was present in Parkinsons patients (p = 0.005) but not in controls (p = 0.65). Weaker gBOLD-CSF coupling in Parkinsons patients also was associated with a thinner right entorhinal cortex (Spearmans correlation = - 0.36; p = 0.012), an early structural change often seen in Alzheimers. ConclusionsThe decoupling between global brain activity and associated CSF flow is related to Parkinsons cognitive impairment.

neuroscience↗