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Beverly L. Davidson, Ph.D.

Beverly L. Davidson, Ph.D.

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Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
The Children's Hospital of Philadelphia
3501 Civic Center Boulevard, 5060 CTRB
Philadelphia, PA 19104
Office: 267-426-0929
Fax: 215-590-3660
Education:
B.S. (Biology Major/Chemistry Minor; High Distinction)
Nebraska Wesleyan University, 1981.
Ph.D. (Biological Chemistry)
University of Michigan, 1987.
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Description of 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 (https://sispotr.icts.uiowa.edu/ ; 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.

Selected Publications

Carmona V, Cunha-Santos J, Onofre I, Simoes A, Vijayakumar U, Davidson BL, Pereira de Almeida L.: Unravelling endogenous MicroRNAs system dysfunction as a new pathophysiological mechanism in Machado-Joseph disease. Mol Ther 25(4): 1038-1055, Feb 2017.

Kim Y-C, Miller A, Lins LCRF, Han W-W, Keiser MS, Davidson BL, Nandakumar S.: RNA interference of human alpha-synuclein in mouse. Front Neurol Jan 2017 Notes: 10.3389/fneur2017.00013.

Monteys, AM, Ebanks SA, Keiser MS, Davidson BL: CRISPR/Cas9 editing of the mutant Huntingtin allele in vitro and in vivo. Mol Ther 25(1): 12-23, Jan 2017.

Dissen GA, Adachi K, Lomniczi A, Chatkupt T, Davidson BL, Nakai H, Ojeda SR: Engineering as a gene silencing viral construct that targets the cat hypothalamus to induce permanent sterility: An update. Reprod Dom Anim Nov 2016 Notes: doi: 10.111/rda. 12834 [Epub ahead of print]

Keiser MS, Mas Monteys A, Corbau R, Gonzalez-Alegre P, Davidson BL.: RNAi prevents and reverses phenotypes induced by mutant human ataxin-1. Annals of Neurology 80(5): 754-765, Nov 2016 Notes: NIHMS820622; DOI: 10.1002/ana.24789.

Ramachandran S, Coffin SL, Tang T-Y, Jobaliya CD, Spengler RM, Davidson BL: cis-Acting sing nucleotide polymorphisms alter Micro RNA-mediated regulation of human brain expressed transcripts. Hum Mol Genet 25(22): 4939-4950, Sept 2016 Notes: Free text link: http://hmg.oxfordjournals.org/content/early/2016/10/18/hmg.ddw317.long

Spenger RM, Zhang X, Cheng C, McLendon JM, Skeie JM, Johnson FL, Davidson BL, Boudreau RL: Elucidation of transcriptome-side micro RNA binding sites in human cardiac tissues by Ago2 HITS-CLIP. Nucleic Acids Research 44(15): 7120-7131, Sept 2016 Notes: Advance Access published July 14, 2016 (Nucl. Acids Res.-2016-Spengler-nar_gkw640.pdf).

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): Transcriptome sequencing reveals aberrant alternative splicing in Huntington's disease. Hum Mol Genet 15(25): 3545-3466, Aug 2016 Notes: pil: ddw187. [Epub ahead of print]. Free full advance access: http://hmg.oxfordjournals.org/content/early/2016/07/03/hmg.ddw187.long.

Thompson LM, Ochaba J, Mas Monteys A, O'Rourke JG, Reidling JC, Steffan JS, Davidson BL: PIAS1 regulates mutant Huntingtin accumulation and Huntington's disease-associated phenoytypes in vivo. Neuron 90(3): 507-520, May 2016.

Davidson BL, Lee B: Gene therapy grows up (and moves out of the house). Hum Mol Genet 25(R1): R1, March 2016.

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Last updated: 06/09/2017
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