About

Professor Steven F. Dowdy, Ph.D., is affiliated with the University of California San Diego in the Department of Cellular and Molecular Medicine. The page does not provide specific details about his research focus, background, or key contributions. The content primarily lists lab members, postdoctoral fellows, students, and administrative contacts, without elaborating on his scientific work or biography.

Research topics

• Biology
• Computational biology
• Cell biology
• Biochemistry
• Pathology
• Neuroscience
• Medicine
• Genetics

Selected publications

• Antisense oligonucleotides directed against <i>App</i> and <i>Rab5</i> normalized endosomal Rab activity and reversed DS‐AD‐linked degenerative phenotypes in the Dp16 mouse model of Down syndrome

  Alzheimer s & Dementia · 2025-05-01 · 7 citations

  articleOpen access

  INTRODUCTION: Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS-AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS-AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11. METHODS: We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS-AD mouse model was treated with a mouse App-specific antisense oligonucleotide (App-ASO) and Rab5-specific ASOs targeting Rab5a and Rab5b. RESULTS: App-ASO treatment normalized full-length APP (fl-APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5-ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS-AD-linked pathologies. DISCUSSION: These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO-based strategies targeting APP or Rab5 to counteract DS-AD features. HIGHLIGHTS: App-ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5-ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP-linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App-ASO or Rab5-ASOs reversed established pathological phenotypes in Dp16 mice.

  PublisherOA PDFDOI

• Stereopure ASOs: An unanticipated increase in selectivity for targeting mutant HTT

  Molecular Therapy — Nucleic Acids · 2024-08-28 · 1 citations

  articleOpen accessSenior author
  PublisherDOI

• Reply to: Ptbp1 deletion does not induce astrocyte-to-neuron conversion

  Nature · 2023-06-07 · 19 citations

  letter
  PublisherDOI

• Data from Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

  2023-03-30

  preprintOpen access

  &lt;div&gt;Abstract&lt;p&gt;Transcription factors play a central role in malignant transformation by activating or repressing waves of downstream target genes. Therapeutic targeting of transcription factors can reprogram cancer cells to lose their advantages in growth and survival. The BCL6 transcriptional repressor plays a central role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and controls downstream checkpoints, including the p53 tumor suppressor gene. We report that a specific inhibitor of BCL6 called BPI can trigger a p53 response in DLBCL cells. This was partially due to induction of p53 activity and partially due to relief of direct repression by BCL6 of p53 target genes. BPI could thus induce a p53-like response even in the presence of mutant p53. Moreover, sequential BCL6 peptide inhibitors followed by p53 peptide or small-molecule activators provided a more powerful antilymphoma effect than either treatment alone by maximally restoring p53 target gene expression. Therefore, tandem targeting of the overlapping BCL6 and p53 transcriptional programs can correct aberrant survival pathways in DLBCL and might provide an effective therapeutic approach to lymphoma therapy. [Cancer Res 2008;68(9):3361–9]&lt;/p&gt;&lt;/div&gt;

  PublisherDOI

• Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?

  RNA · 2023 · 132 citations

  1st authorCorresponding
  • Biology
  • Cell biology
  • Computational biology

  With over 15 FDA approved drugs on the market and numerous ongoing clinical trials, RNA therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have shown great potential to treat human disease. Their mechanism of action is based entirely on the sequence of validated disease-causing genes without the prerequisite knowledge of protein structure, activity or cellular location. In contrast to small molecule therapeutics that passively diffuse across the cell membrane's lipid bilayer, RNA therapeutics are too large, too charged, and/or too hydrophilic to passively diffuse across the cellular membrane and instead are taken up into cells by endocytosis. However, endosomes are also composed of a lipid bilayer barrier that results in endosomal capture and retention of 99% of RNA therapeutics with 1% or less entering the cytoplasm. Although this very low level of endosomal escape has proven sufficient for liver and some CNS disorders, it is insufficient for the vast majority of extra-hepatic diseases. Unfortunately, there are currently no acceptable solutions to the endosomal escape problem. Consequently, before RNA therapeutics can be used to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a nontoxic manner.

  PublisherOA PDFDOI

• Design, Synthesis, and Biochemical Analysis of a Molecule Designed to Enhance Endosomal Escape

  The AAPS Journal · 2023-12-22 · 8 citations

  articleSenior author
  PublisherDOI

• Supplementary Materials from Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

  2023-03-30

  preprintOpen access

  Supplementary Materials from Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

  PublisherDOI

• Long-Term Exposure of Cells to Cdk4 Inhibitor Palbociclib Leads to Chromosomal Aberrations

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-08-11 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Breast cancers are often driven by mutations, alterations and activation of cell cycle regulatory proteins, including the retinoblastoma tumor suppressor protein (Rb), cyclin E and cyclin-dependent kinases (Cdks), especially cyclin D:Cdk4/6 complexes. There are currently three FDA approved Cdk4/6 inhibitors (Cdk4i) for treating breast cancer. The standard treatment protocol is 21 days of continuous Cdk4i treatment, followed by a 7 day cessation period and then repeating the 28 day protocol. We asked the question of what happens to cells that reenter the cell cycle during the 7 day Cdk4i cessation period. Using RPE1 cells containing visual reporter endogenous histone 2B and p27 genes tagged with eGFP and mCherry, we treated the cells with a Cdk4i, Palbociclib for 1 to 42 days that spanned the clinical exposure, followed by drug release (washout) and video microscopic analysis. Surprisingly, we found that as little as 4 days of Cdk4i treatment and release resulted in a significant increase in micronuclei and multinucleated cells that had reentered the cell cycle. The peak chromosomal aberration occurred between 14 and 35 days, a timing that spans the clinical dosing regimen.These observations raise questions concerning the potential that cycling patients on and off of Cdk4 inhibitors may generate gross chromosomal changes to tumor cells that reenter the cell cycle during the 7 day clinical cessation (washout) period and thereby increase the potential to initiate secondary oncogenic events.

  PublisherOA PDFDOI

• Data from Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

  2023-03-30

  preprintOpen access

  &lt;div&gt;Abstract&lt;p&gt;Transcription factors play a central role in malignant transformation by activating or repressing waves of downstream target genes. Therapeutic targeting of transcription factors can reprogram cancer cells to lose their advantages in growth and survival. The BCL6 transcriptional repressor plays a central role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL) and controls downstream checkpoints, including the p53 tumor suppressor gene. We report that a specific inhibitor of BCL6 called BPI can trigger a p53 response in DLBCL cells. This was partially due to induction of p53 activity and partially due to relief of direct repression by BCL6 of p53 target genes. BPI could thus induce a p53-like response even in the presence of mutant p53. Moreover, sequential BCL6 peptide inhibitors followed by p53 peptide or small-molecule activators provided a more powerful antilymphoma effect than either treatment alone by maximally restoring p53 target gene expression. Therefore, tandem targeting of the overlapping BCL6 and p53 transcriptional programs can correct aberrant survival pathways in DLBCL and might provide an effective therapeutic approach to lymphoma therapy. [Cancer Res 2008;68(9):3361–9]&lt;/p&gt;&lt;/div&gt;

  PublisherDOI

• Supplementary Materials from Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

  2023-03-30

  preprintOpen access

  Supplementary Materials from Sequential Transcription Factor Targeting for Diffuse Large B-Cell Lymphomas

  PublisherOA PDFDOI

Recent grants

• Treating Adenovirus Conjunctivitis with Next-Gen siRNN RNAi Prodrugs

  NIH · $453k · 2017–2020

• NIH Grant R21CA195191

  NIH · $371k · 2017

• Development of Antibody-RNAi Conjugates (ARCs) to Treat Lung Cancer

  NIH · $376k · 2018–2020

• NIH Grant R01CA096098

  NIH · $1.2M · 2006

• NIH Grant R21CA169849

  NIH · $366k · 2015

Frequent coauthors

• Michelle Becker‐Hapak

  16 shared

• Sergei A. Ezhevsky

  Sanford Burnham Prebys Medical Discovery Institute

  14 shared

• Jehangir S. Wadia

  Johnson & Johnson (United States)

  13 shared

• Hikaru Nagahara

  Saiseikai Ibaraki Hospital

  13 shared

• Bernard E. Weissman

  12 shared

• Peter Lönn

  Uppsala University

  12 shared

• Manuel Kaulich

  12 shared

• Adita M. Vocero-Akbani

  Howard Hughes Medical Institute

  11 shared

Education

• PhD, Molecular Genetics

  University of California, Irvine

  1990