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Dive into the research topics where Tiffany Butts is active.

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Featured researches published by Tiffany Butts.


Molecular Therapy | 2012

Successful Regional Delivery and Long-term Expression of a Dystrophin Gene in Canine Muscular Dystrophy: A Preclinical Model for Human Therapies

Zejing Wang; Rainer Storb; Christine L. Halbert; Glen B. Banks; Tiffany Butts; Eric Finn; James M. Allen; A. Dusty Miller; Jeffrey S. Chamberlain; Stephen J. Tapscott

Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a group of skeletal muscles in dystrophic dogs given a brief course of commonly used immunosuppressants. Robust c-µdys expression was obtained for at least two years and was associated with molecular reconstitution of the dystrophin-glycoprotein complex (DGC) at the muscle membrane. Importantly, c-µdys expression was maintained for at least 18 months after discontinuing immunosuppression. The results obtained in a relevant preclinical model of DMD demonstrate feasibility of widespread AAV-mediated muscle transduction and transgene expression in the presence of transient immunosuppression to achieve molecular reconstitution that can be directly translated to human trials.


Archive | 2012

Original ArticleSuccessful Regional Delivery and Long-term Expression of a Dystrophin Gene in Canine Muscular Dystrophy: A Preclinical Model for Human Therapies

Zejing Wang; Rainer Storb; Christine L. Halbert; Glen B. Banks; Tiffany Butts; Eric Finn; James M. Allen; A. Dusty Miller; Jeffrey S. Chamberlain; Stephen J. Tapscott

Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a group of skeletal muscles in dystrophic dogs given a brief course of commonly used immunosuppressants. Robust c-µdys expression was obtained for at least two years and was associated with molecular reconstitution of the dystrophin-glycoprotein complex (DGC) at the muscle membrane. Importantly, c-µdys expression was maintained for at least 18 months after discontinuing immunosuppression. The results obtained in a relevant preclinical model of DMD demonstrate feasibility of widespread AAV-mediated muscle transduction and transgene expression in the presence of transient immunosuppression to achieve molecular reconstitution that can be directly translated to human trials.


Transplantation | 2012

Long-term tolerance to kidney allografts after induced rejection of donor hematopoietic chimerism in a preclinical canine model.

Scott S. Graves; David W. Mathes; George E. Georges; Christian S. Kuhr; Jeff Chang; Tiffany Butts; Rainer Storb

Background Allogeneic hematopoietic cell transplantation provides a reliable method for inducing tolerance toward solid organ grafts. However, this procedure can result in graft-versus-host disease, thereby limiting its application. Here, we test the hypothesis that mixed chimerism can be intentionally reverted to host hematopoiesis without rejection of a kidney graft. Methods Recipient dogs were given 2-Gy total-body irradiation (TBI) before and a short course of immunosuppression after marrow infusion from dog leukocyte antigen–identical littermates. All dogs achieved stable mixed chimerism. After a mean of 20 weeks, one cohort of dogs received kidney transplants from their respective marrow donors. Subsequently, recipients were reconditioned with 2-Gy TBI and given autologous granulocyte colony-stimulating factor–mobilized leukocytes (recipient leukocyte infusion [RLI]) that had been collected before marrow transplantation. Results Dogs receiving a second TBI and RLI without a kidney transplant rejected their donor hematopoietic graft within 3 weeks. Dogs that received kidney grafts, followed by a second TBI and RLI, rejected their marrow graft without rejecting their transplanted kidneys for periods greater than 1 year. Conclusion Mixed chimerism may be clinically reverted to 100% recipient without rejection of a kidney allograft. This finding may have application toward minimizing the risk of graft-versus-host disease in solid organ transplantation patients given hematopoietic cell transplantation from human leukocyte antigen–identical donors.


Gene Therapy | 2014

Elimination of contaminating cap genes in AAV vector virions reduces immune responses and improves transgene expression in a canine gene therapy model

Zejing Wang; Christine L. Halbert; Donghoon Lee; Tiffany Butts; Stephen J. Tapscott; Rainer Storb; Miller Ad

Animal and human gene therapy studies utilizing AAV vectors have shown that immune responses to AAV capsid proteins can severely limit transgene expression. The main source of capsid antigen is that associated with the AAV vectors, which can be reduced by stringent vector purification. A second source of AAV capsid proteins is that expressed from cap genes aberrantly packaged into AAV virions during vector production. This antigen source can be eliminated by the use of a cap gene that is too large to be incorporated into an AAV capsid, such as a cap gene containing a large intron (captron gene). Here, we investigated the effects of elimination of cap gene transfer and of vector purification by CsCl gradient centrifugation on AAV vector immunogenicity and expression following intramuscular injection in dogs. We found that both approaches reduced vector immunogenicity and that combining the two produced the lowest immune responses and highest transgene expression. This combined approach enabled the use of a relatively mild immunosuppressive regimen to promote robust micro-dystrophin gene expression in Duchenne muscular dystrophy-affected dogs. Our study shows the importance of minimizing AAV cap gene impurities and indicates that this improvement in AAV vector production may benefit human applications.


Plastic and Reconstructive Surgery | 2014

Abstract 12: Achieving Tolerance in a Mismatched VCA Transplant While Reducing the Risk of GVHD

Bruce Swearingen; Jeff Chang; David W. Mathes; Tiffany Butts; Scott S. Graves; Rainer Storb

BaCkground: Transplantation of vascularized composite allografts (VCA) to reconstruct devastating facial injuries and lost extremities offer the opportunity to truly restore both form and function. Due to the necessity of life-long immunosuppression, the clinical application of these techniques is limited. One promising method of inducing tolerance to an organ allograft is the development of mixed chimerism. We have previously demonstrated that a non-myeloablative stem cell transplant can lead to tolerance in a mismatched dog model. However, the application of this protocol has been limited by graft-versus-host disease (GVHD). We have observed several animals that, after an initial period of donor cell engraftment, lost their stem cell allograft but remained tolerant to the VCA. Conversely, animals that retained persistent donor cell chimerism inevitably developed GVHD. The hypothesis for this study was that our non-myeloablative hematopoietic stem cell transplant protocol could be used to induce tolerance to a recipient VCA without the need for persistent donor cell chimerism. To more closely mimic the clinical setting, our protocol was modified to an extended tapered cessation of immunosuppression.


Molecular Therapy | 2015

398. Sustained Expression of a Canine Micro-Dystrophin Lead To Improvement of Limb Muscle Function in Dystrophic Dogs Following Large Scale AAV-Mediated Treatment

Christine L. Halbert; Melissa A. Goddard; Donghoon Lee; David L. Mack; Tiffany Butts; Robert W. Grange; Mackenzie Johnson; Rainer Storb; Dusty Miller; Jeffrey S. Chamberlain; Stephen J. Tapscott; Martin K. Childers; Zejing Wang

Adeno-associated viral (AAV) vectors as gene delivery vehicles have shown promise both in preclinical studies and clinical trials for a number of acquired and inherited diseases, including Duchenne Muscular Dystrophy (DMD). Studies have shown that host immune responses against AAV can compromise vector delivery and prevent sustained therapeutic gene expression in animal models and humans. We developed and demonstrated a novel AAV production system that prevents aberrant packaging of the AAV capsid (cap) genes. Compared to conventional AAV production methods, our new approach eliminates unwanted in vivo expression of AAV capsid proteins and significantly reduces host immune responses. Here, we demonstrated in a pilot study that we were able to reduce a tripledrug immunosuppressive regimen to a mild 2-drug regimen while retaining sustained canine micro-dystrophin expression in CXMD dogs following large scale delivery of an AAV vector carrying the canine micro-dystrophin to a group of muscles in the hind limb.Amelioration of muscle pathology as a result of sustained expression of the therapeutic gene was demonstrated by histological analysis of muscle tissues and by non-invasive magnetic resonance imaging (MRI). Further, we determined functional benefit of micro-dystrophin expression by muscle force measurement and gait analysis. Significant improvement in muscle force, as indicated by more than 100% increase in strength (torque), was observed in the treated limb compared to that in the untreated limb. In conclusion, by combining newly improved AAV production and mild clinically applicable immunosuppression, the finding of long term robust dystrophin expression in CXMD dogs’ limb with significant functional improvement opens the possibility of translating these strategies to a human DMD trial, which can improve patients’ immediate quality of life.


Plastic and Reconstructive Surgery | 2014

Achieving Tolerance in a Mismatched VCA Transplant While Reducing the Risk of GVHD: The Goal of Transient Chimerism

Bruce Swearingen; Jeff Chang; Tiffany Butts; Scott S. Graves; Rainer Storb; David W. Mathes

BACKGROUND: Transplantation of vascularized composite allografts (VCA) offers the opportunity to restore form and function. Clinical application is limited due to the necessity of life-long immunosuppression. One promising method of inducing tolerance to an organ allograft is the development of mixed chimerism. We have demonstrated that a nonmyeloablative stem cell transplant can lead to tolerance in a mismatched dog model. However, the application of this protocol has been limited by graft-versus-host disease (GVHD). We have observed several animals that, after an initial period of donor cell engraftment, lost their stem cell allograft but remained tolerant to the VCA. Conversely, animals that retained persistent donor cell chimerism inevitably developed GVHD. The hypothesis for this study was that our non-myeloablative hematopoietic stem cell transplant protocol could be used to induce tolerance to a recipient VCA without the need for persistent donor cell chimerism.


Biology of Blood and Marrow Transplantation | 2013

Comparing high and low total body irradiation dose rates for minimum-intensity conditioning of dogs for dog leukocyte antigen-identical bone marrow grafts.

Scott S. Graves; Barry E. Storer; Tiffany Butts; Rainer Storb


Transplantation | 2014

Extended Immunosuppressive Therapy in a Non-Myeloablative Conditioning Regimen: Achieving Tolerance in VCA While Reducing Risk of GVHD.: Abstract# D2814

Bruce J Swearingen; Jeff Chang; Tiffany Butts; Scott S. Graves; Storb R; David W. Mathes


Transplantation | 2014

Achieving Tolerance in a Mismatched VCA Transplant While Reducing The Risk of GVHD: Goal of Transient Chimerism.: Abstract# D2825

Bruce J Swearingen; Jeff Chang; Tiffany Butts; Scott S. Graves; Storb R; David W. Mathes

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Rainer Storb

Fred Hutchinson Cancer Research Center

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Scott S. Graves

Fred Hutchinson Cancer Research Center

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Jeff Chang

University of Washington

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Bruce Swearingen

Fred Hutchinson Cancer Research Center

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Christine L. Halbert

Fred Hutchinson Cancer Research Center

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Stephen J. Tapscott

Fred Hutchinson Cancer Research Center

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Storb R

University of Washington

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Zejing Wang

University of Washington

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Billana Hwang

Fred Hutchinson Cancer Research Center

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