About

Beverly L. Davidson, Ph.D., is a Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. She serves as the Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia and is the Chief Scientific Strategy Officer at the Children's Hospital of Philadelphia Research Institute. Her research focuses on genetic diseases affecting the brain, studying the mechanisms by which mutant gene products contribute to disease and exploring why certain brain regions are more susceptible. Her team employs advanced molecular methods, sequencing, and imaging modalities in animal models to develop next-generation therapeutics for inherited disorders, including engineering novel gene therapy vector capsids and cargo to achieve tissue and cell type-specific treatments.

Research topics

• Biology
• Genetics
• Molecular biology
• Cell biology
• Medicine

Selected publications

• Efficacy of AAV-mediated gene therapy in a sheep model of CLN1 disease

  Molecular Genetics and Metabolism · 2026-02-01

  article
  PublisherDOI

• Temporal single-cell atlas of full-length Huntington’s disease mouse model defines stage-specific signatures of corticostriatal dysfunction

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-08

  articleOpen accessSenior authorCorresponding

  Huntington's disease involves progressive corticostriatal dysfunction; however, the timing of region-specific transcriptional changes remains unresolved at cellular resolution. Here, we provide a temporal single-nucleus transcriptomic atlas of striatum and motor cortex from zQ175 knock-in mice at 6 and 18 months. This full-length Huntingtin model enables staging of progressive circuit dysfunction. Striatal projection neurons show extensive early dysregulation with progressive striosomal identity erosion, whereas cortical pyramidal neuron dysfunction was layer-specific and coincided with motor symptom onset. By modeling genotype-dependent effects, we distinguish region- and cell type-specific signatures of core disease mechanisms from age-related changes and compensatory adaptations. Integrating gene co-expression and transcription factor regulatory networks, we predict candidate regulators of stage-specific dysfunction. These findings, validated across human HD and mouse model datasets, reveal temporal dynamics of disease pathogenesis in regionally distinct and interconnected neuronal populations, establishing a framework for understanding cell type-selective vulnerability.

  PublisherOA PDFDOI

• Implications of the FDA’s new plausible mechanism framework for the development of a personalized in vivo prime editing platform

  The American Journal of Human Genetics · 2026-03-31

  articleOpen access

  In February 2026, the US Food and Drug Administration (FDA) published a draft guidance on a new plausible mechanism framework for the development and approval of individualized therapies for genetic conditions. Here, we report initial proof-of-concept studies supporting a customizable prime editing platform geared to the treatment of 7 urea cycle disorders (UCDs) and other liver-centered disorders, as well as the outcome of a formal meeting with the FDA to discuss the use of the platform in an "umbrella-of-umbrellas" clinical trial including subjects with any of the 7 UCDs. We anticipate our findings will be of interest to academic investigators and industry sponsors who wish to pursue expeditious FDA approvals of therapies for ultra-rare diseases using the plausible mechanism framework.

  PublisherDOI

• Computational modeling and preclinical validation support targeting somatic instability for Huntington’s disease treatment

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-07

  articleOpen accessSenior authorCorresponding

  ABSTRACT Huntington’s disease (HD) is caused by an expanded CAG trinucleotide repeat within the huntingtin (HTT) gene. Genetic modifiers of disease onset and progression in HD implicate somatic instability (SI) of the expanded CAG repeat as a key pathogenic driver, with MSH3 emerging as a leading therapeutic target. Reducing SI, particularly in the most affected neuronal cell type, medium spiny neurons (MSNs) of the striatum, is thus a rational therapeutic strategy for HD. To inform the development of an SI-targeted therapy, we generated a computational model simulating SI in MSNs to infer therapeutic effects on MSN survival resulting from an intervention that reduces SI. The model takes advantage of HD patient data to predict therapeutic benefit across a range of inherited CAG lengths and ages of intervention, considering the degree of target engagement regionally and per cell. To target SI experimentally, we designed an artificial microRNA to lower MSH3 mRNA (miMSH3) after delivery with AAV-DB-3, a previously described MSN-targeting AAV capsid variant. AAV-DB-3.miMSH3 achieved from 48 to 94% MSH3 mRNA reduction in MSNs of nonhuman primates (NHPs), which, when modeled, would reduce the composite Unified Huntington Disease Rating Scale change over baseline from 50 to over 120% as well as delay motor symptom onset by many years. AAV-DB-3.miMSH3 also showed robust target engagement in vivo with up to 46% reduction in SI in HdhQ111 mice. The integration of preclinical experimental data and the computational model support the translational potential of AAV-DB-3.miMSH3 as a disease-modifying therapy applicable for HD patients with a broad range of inherited repeat lengths. One Sentence Summary Predictive modeling to guide therapeutic targeting of disease modifiers in Huntington’s disease.

  PublisherOA PDFDOI

• Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery

  New England Journal of Medicine · 2026-05-13 · 1 citations

  article

  and expression of a chimeric AAV-PLAG1 transcript.

  PublisherDOI

• An AAV variant selected through NHP screens robustly transduces the brain and drives secreted protein expression in NHPs and mice

  Science Translational Medicine · 2025-05-14 · 9 citations

  articleSenior authorCorresponding

  Recent work has shown that prolonged expression of recombinant proteins after adeno-associated virus (AAV)–mediated delivery of gene therapy to long-lived, ventricle-lining ependymal cells can profoundly affect disease phenotypes in animal models of neurodegenerative diseases. Here, we performed in vivo screens of millions of peptide-modified capsid variants of AAV1, AAV2, and AAV9 parental serotypes in adult nonhuman primates (NHPs) to identify capsids with potent transduction of key brain tissues, including ependyma, after intracerebroventricular injection. Through these screens, we identified an AAV capsid, AAV-Ep + , with markedly increased potency in transducing ependymal cells and cerebral neurons in NHPs. AAV-Ep + ’s potency was conserved in three species of NHP, two mouse strains, and human neurons derived from induced pluripotent stem cells. To apply AAV-Ep + to the treatment of ceroid lipofuscinosis type 2 disease, a lysosomal storage disorder caused by loss-of-function mutations in tripeptidyl-peptidase 1 ( TPP1 ), we used the capsid to package the human TPP1 transgene (AAV-Ep + .hTPP1) and delivered the construct by intracerebroventricular injection into mice lacking TPP1 activity. AAV-Ep + provided robust and therapeutically relevant TPP1 protein concentrations in these mice, significantly improving tremor and life span. In NHPs, high cerebrospinal fluid (CSF) TPP1 concentrations were achieved after intracerebroventricular delivery of AAV-Ep + .hTPP1 at a total dose of 1 × 10 12 viral genomes, which was more than 30× lower than previously reported doses in NHPs. These results suggest that AAV-Ep + may be a potent vector for gene therapy applications where CSF protein expression is required.

  PublisherDOI

• 219 Peptide insertions enhance AAV capsid tropism for airway epithelia

  Journal of Cystic Fibrosis · 2025-10-01

  article
  PublisherDOI

• Author Correction: AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice

  Nature Communications · 2025-10-23 · 1 citations

  articleOpen accessSenior authorCorresponding

  In the version of the article initially published, a reference citation was missing in the first sentence of the Results "Translatability to human targets" section, which now reads "To determine the ability of miAtxn2 to target human ATXN2, we used the 127Q transgenic mouse model of spinocerebellar ataxia type 2, in which mice overexpress mutant human ATXN2 in cerebellar Purkinje cells [Hansen, S.

  PublisherOA PDFDOI

• Scouring the human Hsp70 network uncovers diverse chaperone safeguards buffering TDP-43 toxicity

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-10 · 1 citations

  preprintOpen access

  Cytoplasmic aggregation and concomitant dysfunction of the prion-like, RNA-binding protein TDP-43 underpin several fatal neurodegenerative diseases, including amyotrophic lateral sclerosis. To elucidate endogenous defenses, we systematically scoured the entire human Hsp70 network for buffers of TDP-43 toxicity. We identify 30 J-domain proteins (2 DNAJAs, 10 DNAJBs, 18 DNAJCs), 6 Hsp70s, and 5 nucleotide-exchange factors that mitigate TDP-43 toxicity. Specific chaperones reduce TDP-43 aggregate burden and detoxify diverse synthetic or disease-linked TDP-43 variants. Sequence-activity mapping unveiled unexpected, modular mechanisms of chaperone-mediated protection. Typically, DNAJBs collaborate with Hsp70 to suppress TDP-43 toxicity, whereas DNAJCs act independently. In human cells, specific chaperones increase TDP-43 solubility and enhance viability under proteotoxic stress. Strikingly, spliceosome-associated DNAJC8 and DNAJC17 retain TDP-43 in the nucleus and promote liquid-phase behavior. Thus, we disambiguate a diverse chaperone arsenal embedded in the human proteostasis network that counters TDP-43 toxicity and illuminate mechanistic gateways for therapeutic intervention in TDP-43 proteinopathies.

  PublisherOA PDFDOI

• Current trends in gene therapy to treat inherited disorders of the brain

  Molecular Therapy · 2025-04-03 · 7 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

Recent grants

• Neuroregulatory Mechanisms of PIAS1 and Implications for Huntington's Disease

  NIH · $1.8M · 2015–2020

• NIH Grant R21DA025132

  NIH · $300k · 2011

• RNAi Therapy for Spinocerebellar Ataxia Type 1

  NIH · $1.1M · 2016–2016

• NIH Grant R01HD033531

  NIH · $3.2M · 2008

• NIH Grant RC1NS068280

  NIH · $933k · 2012

Frequent coauthors

• Qian Liu

  Zhejiang Gongshang University

  84 shared

• Colleen S. Stein

  Fraternal Order of Eagles

  61 shared

• Inês Martins

  University of Iowa

  51 shared

• Donald D. Heistad

  University of Iowa

  44 shared

• Alex Mas Monteys

  Philadelphia University

  39 shared

• Ryan L. Boudreau

  University of Iowa

  38 shared

• Luis Tecedor

  Children's Hospital of Philadelphia

  38 shared

• William N. Kelley

  University of Maryland, Baltimore

  38 shared

Education

• Postdoctoral Fellow, Molecular Genetics

  University of Michigan

  1990

• Ph.D., Biological Chemistry

  University of Michigan

  1987

• B.S., Biology

  Nebraska Wesleyan University

  1981