Beverly L. Davidson, PhD

Professor of Pathology and Laboratory Medicine
Professor of Genetics
University of Pennsylvania Perelman School of Medicine
Arthur V. Meigs Chair in Pediatrics at CHOP

Contact InformationThe Children's Hospital of Philadelphia
3501 Civic Center Boulevard, 5060 CTRB
Philadelphia, PA 19104
Office: 267-426-0929
Fax: 215-590-3660


Research Expertise

My research addresses fundamental questions in the pathogenesis and therapy of hereditary neurogenetic diseases and the role of noncoding RNAs in neural development. In studies focused on the recessively inherited lysosomal storage and dominantly inherited polyglutamine repeat diseases we take advantage of gain-of and loss-of function approaches using viral vectors. In studies on noncoding RNAs we use cell, rodent and human tissues and methodologies designed to test their roles in development and disease pathogenesis. My long term objective is to contribute fundamentally to understanding how the brain works, and to use this knowledge to guide therapy development for fatal brain diseases.

I. Lysosomal storage diseases.
Collectively, the lysosomal storage diseases are a major health problem. They affect 1 in 10,000 live births, and 65% of cases demonstrate severe neuropathologies and behavioral deficits. Exciting progress in translating enzyme replacement therapy from animal models to patients has led to ‘cures’ for some lysosomal storage diseases in which systemic involvement is the major problem. However, no therapies exist for the central nervous system component since systemically delivered enzyme does not reach the brain. My past and future aims are to meet this challenge by understanding disease pathogenesis in brain in relevant models, and testing how brain-directed gene transfer or small molecule therapies impacts these phenotypes. My lab studies two groups of lysosomal storage diseases, the mucopolysaccharidoses (MPS) and the neuronal ceroid lipofuscinoses, more specifically MPS VII and neuronal ceroid lipofuscinoses types 2 and 3 (CLN2 and CLN3).
Gene transfer to understand basic disease mechanisms and potential therapies. The mucopolysaccharidoses and CLN2 result from the absence or reduced activity of lysosomal hydrolases. We know that the progressive brain pathology eventually affects most brain regions. Through earlier work we also know that genetic correction of all deficient cells is not required. This is because the enzymes deficient in the MPS and CLN2 reach the lysosome in two ways. One is direct trafficking to the lysosome following translation. The second method is by secretion and endocytosis and subsequent trafficking to the lysosome. If endocytosis by non-genetically corrected cells occurs, the lysosomal pathology in that cell resolves by ‘cross-correction’. In earlier work, my laboratory tested the hypothesis that therapies initiated after disease onset can reverse behavioral and neuropathological measures using animal models of lysosomal storage disease. We showed that there was a time window of reversibility, a finding that has relevance to other lysosomal storage diseases with brain involvement.
The most direct means to intercede in the progressive brain disease of lysosomal storage disorders is to supply the enzyme directly to the brain. To solve this difficult problem, we developed creative approaches to achieve widespread brain delivery. For example, we found earlier that recombinant protein within CSF could penetrate the underlying brain parenchyma of diseased mice. We identified vectors derived from the nonpathogenic adeno-associated virus that could selectively and efficiently transduce ependymal cells lining the brain ventricles following intracranial injection. Using this vector, we fully reversed disease in a MPS VII mouse model, and now have ongoing studies in the CLN2 dog model. Preliminary data from that work shows an impact on disease onset and progression. Our results in these models have general relevance because they suggest that intrathecal enzyme pumps (initiated by BioMarin for CLN2), or enzyme or other recombinant proteins supplied from ependymal cells via gene therapy, may globally improve CNS pathology. Indeed we extended this approach for protein delivery to animal models of Alzheimer’s disease. We found, in collaboration with colleagues at MGH, that secretion of the protective form of ApoE (ApoE2) could substantially reverse AD-like brain pathologies in mouse models.
In addition to directed enzyme delivery to the brain, we have pioneered re-engineering AAVs for brain delivery after systemic administration and shown efficacy in the MPS VII and CLN2 mouse models. We are now also applying this approach to the AD mouse models and large animal models of lysosomal storage disease.
II. Dominant neurogenetic diseases
Polyglutamine repeat (CAG-repeat) expansion diseases are dominant, fatal progressive neurodegenerative diseases with an incidence as high as 1 in 20,000. Adults are most often affected, with age of onset in reverse correlation with the length of polyglutamine expansion. The fundamental problem is ‘how does one reduce gene expression?’ Our recent work shows that RNA interference (RNAi), coupled with the efficiency of viral mediated delivery may be a viable approach.
We used mouse models of spinocerebellar ataxia type 1 (SCA1) and Huntington’s disease (HD) to test our hypotheses. SCA1 and HD represent two distinct polyglutamine repeat expansion diseases affecting different brain regions and due to CAG-expansion in ataxin-1 and huntingtin, respectively. The mouse models display many important disease characteristics including abnormal behavior and neuropathology, and provided a valid platform for us to assess the efficacy, longevity, and safety of RNAi.
In early work, we provided the first in vivo demonstration of RNAi efficacy in SCA1 and HD models. In these studies we used short hairpin RNAs (shRNAs) and have since engineered RNAi triggers that mimic endogenous microRNAs (miRNAs). These tools show improved utility, including reduced toxicity. Further, to improve safety we developed a web-based design tool (siSPOTR) for generating miRNAs with minimal off-targets ( ; we are in the process of moving the site to CHOP servers.) Our preclinical work, in SCA1 and HD, have now progressed to safety testing in nonhuman primates. Excitingly the delivery approaches are scalable to the primate brain, and we see silencing activity without toxicity. We envision moving this work to Phase I clinical trials in the next 12-24 months. The SCA1 work in particular has paved the way for further application to SCA2 (safety testing done), SCA7 (safety and efficacy done), SCA3 (in collaboration with Henry Paulson, U Mich) and SCA6 (in collaboration with Edgar Rodriguez, U Iowa).
More recently, we are examining the Cas9/CRISPR system for gene editing or allele specific repression. This latter approach requires engineering a nuclease deficient Cas9 for directed DNA binding and repression of the disease allele.

III. Noncoding RNAs in development and disease.
As we embarked on exploiting the pathway of RNA interference for therapeutic use, it became obvious that there was a lack of understanding as to how noncoding RNAs in general, and miRNAs in particular, contribute to neural development and disease pathogenesis. We initiated studies to understand the global importance of miRNAs in brain development using mice deficient in key enzymes in the RNA pathway, and assessed how miRNAs were dysregulated in mouse models of disease. Most recently, we have optimized protocols that allow us to query which noncoding RNAs are engaged in post-transcriptional gene regulation in human brain. We are now extending this work to determine if miRNAs may differ in disease, in distinct brain regions, and among the primate species. This is an exciting time to be in the RNA world and our group has a unique opportunity to make contributions to this field as it relates to human brain diseases and central nervous system function.



B.S. (Biology Major/Chemistry Minor; High Distinction), Nebraska Wesleyan University, 1981
Ph.D. (Biological Chemistry), University of Michigan, 1987

Specialty Certification

Postgraduate Training

Research Assistant, University of Nebraska, Nebraska, 1982-1983
Postdoctoral Fellow, University of Michigan, Michigan, 1988-1988
Research Investigator, University of Michigan, Michigan, 1990-1992
Assistant Research Scientist, University of Michigan, Michigan, 1992-1994

Awards and Honors

President Scholarship Award, 1977-1981
Beta Beta Beta Biology Honorary Society, 1979
Phi Kappa Phi Honor Society, 1980
VI International Symposium on Human Purine and Pyrimidine Metabolism, 1988
Fellow, American Association for the Advancement of Science, 2006
Carver Research Program of Excellence, University of Iowa, 2007-2014
Regents Faculty Excellence Award, 2007
Mathilde Solowey Award, National Institutes of Health, 2008
Eureka Award, National Institutes of Health, 2008
Distinguished Graduate Lecture, University of Michigan Dept of
Biological Chemistry, Ann Arbor, MI, 2011
AANP, SJ DeArmond Lecture, Seattle, WA, 2011
Innovator Award, University of Iowa, 2012
Inventor Award, University of Iowa, 2013
Arthur V. Meigs Chair in Pediatrics, The Children's Hospital of Philadelphia, 2014-Present
Recipient, The Leslie Gehry Prize for Innovation in Science, Hereditary Disease Foundation, 2015
Member, American Academy of Arts and Sciences, 2017

Memberships and Professional Organizations

Mental Retardation Research Committee, NICHD, 1995 - 1999
NIH Study Sections, 1995 - Present
National Gene Vector Laboratory Scientific Review Board, 1996 - 2007
American Society for Cell and Gene Therapy (ASGCT), 1997 - Present
Board of Directors, American Society for Gene Therapy, 2000 - 2003
Hunters Hope, Scientific Advisory Board, 2000 - 2002
Batten Disease Support and Research Association, Scientific Advisory Board, 2000 - Present
Amytrophic Lateral Sclerosis Association, Study Section, 2000 - 2003
Scientific Advisory Board, Oxford Biomedica Inc, 2001 - 2006
TIGET Site Visit Team, Milan, Italy, 2002 - 2002
Sirna Therapeutics, 2004 - 2007
American Society for Gene Therapy, 2005 - 2011
Sirna Therapeutics, 2006 - 2008
TIGET Site Visit Team, Milan, Italy, 2006 - 2006
Hereditary Disease Foundation, 2006 - 2009
Robert Packard Center for ALS Research at Johns Hopkins, 2007 - Present
Scientific Advisory Board, Scientific Committee, Comitato Telethon Fondazione, 2007 - 2010
Centre de Genomica Regulacio, Barcelona Spain, 2007 - Present
TIGET Site Visit Team, Milan, Italy, 2007 - 2007
Wellstone Muscular Dystrophy Center Scientific Advisory Committee,
Minneapolis, MN, 2008 - 2011
TIGET Site Visit Team, Milan, Italy, 2008 - 2008
Oregon National Primate Research Center, 2008 - Present
NCL Foundation, Hamburg, Germany, 2008 - Present
MDRNA, 2009 - 2010
Basal Ganglia Disorders Linnaeus Consortium, Lund, Sweden, 2009 - 2014
Electorate Nominating Committee, Medical Sciences, AAAS, 2009 - 2012
TIGEM Site Visit Team, Naples, Italy, 2009 - Present
TIGET Site Visit Team, Milan, Italy, 2009 - 2009
UMass, 2009 - Present
Scientific Committee, Comitato Telethon Fondazione, 2010 - 2011
Marina Biotech, 2010 - 2012
TAGS study section, NIH, 2011 - Present
TIGEM Site Visit Team, Naples, Italy, 2011 - 2011
BDSRA Scientific Advisory Board, 2011 - Present
nLIFE, 2012 - Present
Medical Sciences, AAAS, 2012 - Present
Hereditary Disease Foundation, 2012 - 2015
Spark Therapeutics, 2013 - Present
NIH Common Fund, 2013 - Present
Member, Blue Ribbon Panel for Review of Intramural Programs, NINDS, NIH, 2014 - Present
Member, External Advisory Committee, Pathophysiology and Global Therapy for Krabbe Disease, Washington University School of Medicine, St. Louis, MO, 2014 - 2015
TIGET Site Visit Team, Milan, Italy, 2014 - 2014
Member, National Advisory Neurological Disorders and Stroke Council, NIH, NINDS, 2014 - Present
NIH Common Fund, 2014 - Present
Member, Scientific Advisory Board, Sarepta Therapeutics, Cambridge, A, 2015 - Present
Member, American Society of Human Genetics, Social Issues Committee, 2015 - Present
Member, Scientific Advisory Board, Intellia Therapeutics, 2015 - Present
Member, Advisory Board, Horizon 2020 Twinning 2015, European Commission, 2015 - Present
Member, Scientific Advisory Committee, Huntington Study Group, 2015 - 2018
Member, Data Safety Monitoring Board, Intrathecal Administration of scAAV9/Jet-GAN for the Treatment of Giant Axonal Neuropathy (NIH Sponsored), 2015 - Present
Member, Medical Research Advisory Bord (MRAB), National Ataxia Foundation, 2015 - Present
Member, Working Group of Council on Diversity, NIH/NINDS, 2016 - Present
Member, Scientific Advisory Board, Friends of Telethon, Italia, 2016 - Present
Member, Scientific Director Search Committee, NIH/NINDS, 2016 - Present
Member, Scientific Advisory Board, Anhui IsoTex (Yun Tai) Biotech, Inc., 2017 - Present

Web Links

Selected Publications

RNA interference of human alpha-synuclein in mouse

Kim Y-C, Miller A, Lins LCRF, Han W-W, Keiser MS, Davidson BL, Nandakumar S., Front Neurol, 2017 (in press)

cis-Acting sing nucleotide polymorphisms alter Micro RNA-mediated regulation of human brain expressed transcripts

Ramachandran S, Coffin SL, Tang T-Y, Jobaliya CD, Spengler RM, Davidson BL, Hum Mol Genet, 2016 (in press), PMID:26738890

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CRISPR/Cas9 editing of the mutant Huntingtin allele in vitro and in vivo

Monteys, AM, Ebanks SA, Keiser MS, Davidson BL, Mol Ther, 2016 (in press)

Unravelling endogenous MicroRNAs system dysfunction as a new pathophysiological mechanism in Machado-Joseph disease

Carmona V, Cunha-Santos J, Onofre I, Simoes A, Vijayakumar U, Davidson BL, Pereira de Almeida L., Mol Ther, 2016 (in press)

Engineering as a gene silencing viral construct that targets the cat hypothalamus to induce permanent sterility: An update

Dissen GA, Adachi K, Lomniczi A, Chatkupt T, Davidson BL, Nakai H, Ojeda SR, Reprod Dom Anim, 2016, PMID:27859771

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RNAi prevents and reverses phenotypes induced by mutant human ataxin-1

Keiser MS, Mas Monteys A, Corbau R, Gonzalez-Alegre P, Davidson BL., Annals of Neurology 80(5): 754-765, 2016, PMID:27686464

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Elucidation of transcriptome-side micro RNA binding sites in human cardiac tissues by Ago2 HITS-CLIP

Spenger RM, Zhang X, Cheng C, McLendon JM, Skeie JM, Johnson FL, Davidson BL, Boudreau RL, Nucleic Acids Research 44(15): 7120-7131, 2016, PMID:27418678

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Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease

Lin L, Park JW, Ramachandran S, Zhang Y, Tseng YT, Shen S, Waldvogel H Curtis M, Faull R, Troncoso J, Ross C, Davidson BL*, Xing Y* (joint corresponding authors), Hum Mol Genet 15(25): 3545-3466, 2016, PMID:27378699

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PIAS1 regulates mutant Huntingtin accumulation and Huntington's disease-associated phenoytypes in vivo

Thompson LM, Ochaba J, Mas Monteys A, O'Rourke JG, Reidling JC, Steffan JS, Davidson BL, Neuron 90(3): 507-520, 2016

Gene therapy grows up (and moves out of the house)

Davidson BL, Lee B, Hum Mol Genet 25(R1): R1, 2016