University of Washington
1959 NE Pacific Street, Rm K-236C
Seattle, WA 98195-7720
Phone: (206) 221-4579
Fax: (206) 616-8272
My research program focuses on modulating gene expression in vivo with the goal of developing a treatment for dominant
genetic disease of muscle. My laboratory team seeks to employ an endogenous cell mechanism for fine-tuning gene expression
at the post-transcriptional level, referred to as the RNA interference (RNAi). RNAi is triggered by processing of double-stranded
RNA for sequence-specific gene silencing through direct base pairing with the target mRNA. Development of RNAi expression cassettes
targeting mRNAs that lead to dominant genetic disease in muscle is a main focus of the laboratory. Both high expression level
ubiquitous promoters and tissue-specific promoters are incorporated into adeno-associated virus vectors (AAV) to drive
double-stranded RNA hairpin expression to carry out targeted RNAi. AAV-mediated tissue tropism combined with variations in
muscle promoter-dependent expression are used to fine-tune therapeutic RNAi delivery. The RNAi expression vectors are tested
both in cell cultures and in pre-clinical disease models, with the ultimate goal of preventing the effects of unwanted gene
expression leading to human disease.
The dominant muscular dystrophies that we are studying are facioscapulohumeral muscular dystrophy (FSHD) and myotonic dystrophy (DM), the 2 most common adult muscular dystrophies with a combined prevalence of approximately 1:2400 individuals. Although FSHD and DM are clinically distinct movement disorders, both diseases are caused by genetic defects that lead to production of toxic cell products that can be targeted by RNAi for destruction. Our challenge is to couple timely intervention with a safe and effective therapy. As we learn more about these diseases and the details of the RNAi pathway, we are better able to show feasibility of this approach in complex living organisms. Recent progress in reversing disease in the FRG1 model of FSHD demonstrates proof-of-principle and we are refining this approach for the ultimate goal of producing a therapy for treating dominant genetic disease of muscle and, in general, for treating disease by modulation of gene expression.
Bortolanza, SB, Nonis, A, Sanvito, F, Maciotta, S, Sitia, G, Wei, J, Torrente, I, Di Serio, C, *Chamberlain, JR, and *Gabellini, D: AAV6-mediated systemic shRNA delivery reverses disease in a mouse model of facioscapulohumeral muscular dystrophy. Mol Therapy 2011; doi:10.1038/mt.2011.153. *Chamberlain and Gabellini co-corresponding authors.
Chamberlain, JR, and Chamberlain, JS: Muscling in: Gene therapies for muscular dystrophy target RNA. Nat Medicine 2009; 16:170-171.
Chamberlain JR, Deyle, DR, Schwarze U, Wang P, Hirata RK, Li Y, Byers PH, Russell DW: Gene targeting of mutant COL1A2 allelles in mesenchymal stem cells from individuals with osteogenesis imperfecta. Mol Ther 2008; 16:187-193.
Banks, GB, Combs, AC, Chamberlain, JR, and Chamberlain, JS: Molecular and cellular adaptations to chronic myotendinous strain injury in mdx mice expressing a truncated dystrophin. Hum Mol Genet 2008; 17:3975-3986. PMC2638580
Chamberlain JR, Schwarze U, Wang PR, Hirata RK, Hankenson KD, Pace JM, Underwood RA, Song KM, Sussman M, Byers PH, Russell DW: Gene targeting in stem cells from individuals with osteogenesis imperfecta. Science 2004; 303:1198-1201.
Hirata R, Chamberlain J, Dong R, and Russell DW: Targeted transgene insertion into human chromosomes by adeno-associated virus vectors. Nat Biotechnol 2002; 20:735-738.
Chamberlain JR, Lee Y, Lane WS, and Engelke DR: Purification of the nuclear RNase P holoenzyme complex reveals extensive subunit overlap with RNase MRP. Genes Dev 1998; 12:1678-1690.
Chamberlain JR, Pagán-Ramos E, Kindelberger DK and Engelke DR: An RNase P RNA subunit mutation affects ribosomal RNA processing. Nucleic Acids Res 1996; 24:3158-3166.
Chamberlain JS, Chamberlain JR, Fenwick RG, et al.: Diagnosis of Duchenne and Becker muscular dystrophies by polymerase chain reaction: A multicenter study. JAMA 1992; 267:2609-2615.
Chamberlain JS, Gibbs RA, Ranier JE, Nguyen PN and Caskey CT: Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification. Nucleic Acids Res 1988; 16:11141-11156.
Chamberlain JS, Pearlman JA, Muzny DM, Gibbs RA, Ranier JE, Reeves AA and Caskey CT: Expression of the murine Duchenne muscular dystrophy gene in muscle and brain. Science 1988; 239:1416-1418.