Immuneering Corporation

Cambridge, MA, United States

Immuneering Corporation

Cambridge, MA, United States
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Lee K.B.,Harvard University | Wang J.,Harvard University | Wang J.,Ginkgo BioWorks, Inc. | Palme J.,TU Munich | And 3 more authors.
PLoS Genetics | Year: 2017

In nature, microbes often need to "decide" which of several available nutrients to utilize, a choice that depends on a cell’s inherent preference and external nutrient levels. While natural environments can have mixtures of different nutrients, phenotypic variation in microbes’ decisions of which nutrient to utilize is poorly studied. Here, we quantified differences in the concentration of glucose and galactose required to induce galactose-responsive (GAL) genes across 36 wild S. cerevisiae strains. Using bulk segregant analysis, we found that a locus containing the galactose sensor GAL3 was associated with differences in GAL signaling in eight different crosses. Using allele replacements, we confirmed that GAL3 is the major driver of GAL induction variation, and that GAL3 allelic variation alone can explain as much as 90% of the variation in GAL induction in a cross. The GAL3 variants we found modulate the diauxic lag, a selectable trait. These results suggest that ecological constraints on the galactose pathway may have led to variation in a single protein, allowing cells to quantitatively tune their response to nutrient changes in the environment. © 2017 Lee et al.

Ryskamp D.,University of Texas Southwestern Medical Center | Wu J.,University of Texas Southwestern Medical Center | Geva M.,Teva Pharmaceutical Industries | Kusko R.,Immuneering Corporation | And 3 more authors.
Neurobiology of Disease | Year: 2017

The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated “dopamine stabilizer”, has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca2 + release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca2 + levels by pridopidine was prevented by S1R deletion. To evaluate long-term effects of pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of pridopidine were mediated by S1R and led to normalization of ER Ca2 + release, ER Ca2 + levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with pridopidine, may further contribute to long-term beneficial effects of pridopidine in HD. © 2016

PubMed | Simmons Comprehensive Cancer Center, SCCC, UTSW, Immuneering Corporation and 2 more.
Type: Journal Article | Journal: Cancer cell | Year: 2016

Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and -lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1

Dong J.,U.S. National Institutes of Health | Munoz A.,Johns Hopkins University | Munoz A.,U.S. National Institutes of Health | Kolitz S.E.,Johns Hopkins University | And 8 more authors.
Genes and Development | Year: 2014

Eukaryotic initiator tRNA (tRNAi) contains several highly conserved unique sequence features, but their importance in accurate start codon selection was unknown. Here we show that conserved bases throughout tRNAi, from the anticodon stem to acceptor stem, play key roles in ensuring the fidelity of start codon recognition in yeast cells. Substituting the conserved G31:C39 base pair in the anticodon stem with different pairs reduces accuracy (the Sui- [suppressor of initiation codon] phenotype), whereas eliminating base pairing increases accuracy (the Ssu- [suppressor of Sui-] phenotype). The latter defect is fully suppressed by a Sui- substitution of T-loop residue A54. These genetic data are paralleled by opposing effects of Sui- and Ssu- substitutions on the stability of methionylated tRNAi (Met-tRNAi) binding (in the ternary complex [TC] with eIF2-GTP) to reconstituted preinitiation complexes (PICs). Disrupting the C3:G70 base pair in the acceptor stem produces a Sui- phenotype and also reduces the rate of TC binding to 40S subunits in vitro and in vivo. Both defects are suppressed by an Ssu- substitution in eIF1A that stabilizes the open/POUT conformation of the PIC that exists prior to start codon recognition. Our data indicate that these signature sequences of tRNAi regulate accuracy by distinct mechanisms, promoting the open/POUT conformation of the PIC (for C3:G70) or destabilizing the closed/PIN state (for G31:C39 and A54) that is critical for start codon recognition. © 2014 Dong et al.

Carrero J.A.,University of Washington | Calderon B.,University of Washington | Towfic F.,Immuneering Corporation | Artyomov M.N.,University of Washington | Unanue E.R.,University of Washington
PLoS ONE | Year: 2013

Our ability to successfully intervene in disease processes is dependent on definitive diagnosis. In the case of autoimmune disease, this is particularly challenging because progression of disease is lengthy and multifactorial. Here we show the first chronological compendium of transcriptional and cellular signatures of diabetes in the non-obese diabetic mouse. Our data relates the immunological environment of the islets of Langerhans with the transcriptional profile at discrete times. Based on these data, we have parsed diabetes into several discrete phases. First, there is a type I interferon signature that precedes T cell activation. Second, there is synchronous infiltration of all immunological cellular subsets and a period of control. Finally, there is the killing phase of the diabetogenic process that is correlated with an NF-kB signature. Our data provides a framework for future examination of autoimmune diabetes and its disease progression markers. © 2013 Carrero et al.

Towfic F.,Immuneering Corporation | Funt J.M.,Immuneering Corporation | Fowler K.D.,Immuneering Corporation | Bakshi S.,Teva Pharmaceutical Industries | And 6 more authors.
PLoS ONE | Year: 2014

For decades, policies regarding generic medicines have sought to provide patients with economical access to safe and effective drugs, while encouraging the development of new therapies. This balance is becoming more challenging for physicians and regulators as biologics and non-biological complex drugs (NBCDs) such as glatiramer acetate demonstrate remarkable efficacy, because generics for these medicines are more difficult to assess. We sought to develop computational methods that use transcriptional profiles to compare branded medicines to generics, robustly characterizing differences in biological impact. We combined multiple computational methods to determine whether differentially expressed genes result from random variation, or point to consistent differences in biological impact of the generic compared to the branded medicine. We applied these methods to analyze gene expression data from mouse splenocytes exposed to either branded glatiramer acetate or a generic. The computational methods identified extensive evidence that branded glatiramer acetate has a more consistent biological impact across batches than the generic, and has a distinct impact on regulatory T cells and myeloid lineage cells. In summary, we developed a computational pipeline that integrates multiple methods to compare two medicines in an innovative way. This pipeline, and the specific findings distinguishing branded glatiramer acetate from a generic, can help physicians and regulators take appropriate steps to ensure safety and efficacy. © 2014 Towfic et al.

The disclosure relates to methods of predicting the effects of therapy, designing/conducting a clinical trial, selecting a subject for a clinical trial, selecting a subject for therapy, monitoring a subjects responsiveness to therapy, treating a subject, and predicting effects of anti-CD25 therapy.

The disclosure relates to systems and methods for automated review of genomic data to identify genetic features indicative of a particular disease or condition. The system accesses genomic data of a first cohort of individuals and identifies one or more genes each of which is differentially expressed by individuals in a group having the disease or condition compared with a control group. The system accesses single-nucleotide polymorphism (SNP) data of a second cohort of individuals different from the first cohort and identifies SNPs associated with the disease or condition. The system determines an intersection between the set of identified genes and the SNPs associated with the disease or condition to identify one or more genes that are downregulated due to the disease or condition. Related treatment methods are also included.

Methods for analyzing one or more elements, markers, ligands or other characteristics of the immune system of a body (e.g., of a human or other animal), and based on the analysis, determine a location of disease, identify immune system failure, and/or determine treatments based on disease location or immune system failure. All or a part of the immune system process may be analyzed to identify specific features of the immune system, e.g., which may indicate that the disease will evade the immune system and produce a negative outcome. Therapy may be employed to correct immune system failure rather than addressing the disease directly.

PubMed | Immuneering Corporation
Type: | Journal: Biostatistics (Oxford, England) | Year: 2016

The article by Nygaard et al proposes that applying batch correction approaches to microarray data from studies with unbalanced designs may inadvertently exaggerate the differences observed. In seeking to illustrate their point, Nygaard et al. utilized a dataset (GSE61901) from a study we published (Towfic and others, 2014) and showed that one analysis pipeline utilizing the traditional approach to batch correction (ComBat) yielded over 1000 differentially expressed probesets, while an alternative approach proposed by Nygaard et al (utilizing batch as a fixed effect and averaging technical replicates) recovered 11 differentially expressed probesets.

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