Browsing by Subject "Genetic Therapy"

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Open Access
AAV Gene Therapy for MPS1-associated Corneal Blindness.
(Scientific reports, 2016-02-22) Vance, Melisa; Llanga, Telmo; Bennett, Will; Woodard, Kenton; Murlidharan, Giridhar; Chungfat, Neil; Asokan, Aravind; Gilger, Brian; Kurtzberg, Joanne; Samulski, R Jude; Hirsch, Matthew L
Although cord blood transplantation has significantly extended the lifespan of mucopolysaccharidosis type 1 (MPS1) patients, over 95% manifest cornea clouding with about 50% progressing to blindness. As corneal transplants are met with high rejection rates in MPS1 children, there remains no treatment to prevent blindness or restore vision in MPS1 children. Since MPS1 is caused by mutations in idua, which encodes alpha-L-iduronidase, a gene addition strategy to prevent, and potentially reverse, MPS1-associated corneal blindness was investigated. Initially, a codon optimized idua cDNA expression cassette (opt-IDUA) was validated for IDUA production and function following adeno-associated virus (AAV) vector transduction of MPS1 patient fibroblasts. Then, an AAV serotype evaluation in human cornea explants identified an AAV8 and 9 chimeric capsid (8G9) as most efficient for transduction. AAV8G9-opt-IDUA administered to human corneas via intrastromal injection demonstrated widespread transduction, which included cells that naturally produce IDUA, and resulted in a >10-fold supraphysiological increase in IDUA activity. No significant apoptosis related to AAV vectors or IDUA was observed under any conditions in both human corneas and MPS1 patient fibroblasts. The collective preclinical data demonstrate safe and efficient IDUA delivery to human corneas, which may prevent and potentially reverse MPS1-associated cornea blindness.
Open Access
Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.
(FASEB J, 2013-01) Li, Songtao; Sun, Baodong; Nilsson, Mats I; Bird, Andrew; Tarnopolsky, Mark A; Thurberg, Beth L; Bali, Deeksha; Koeberl, Dwight D
Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.
Open Access
An International Society for Cell and Gene Therapy Mesenchymal Stromal Cells Committee editorial on overcoming limitations in clinical trials of mesenchymal stromal cell therapy for coronavirus disease-19: time for a global registry.
(Cytotherapy, 2022-11) Weiss, Daniel J; Filiano, Anthony; Galipeau, Jacques; Khoury, Maroun; Krampera, Mauro; Lalu, Manoj; Blanc, Katarina Le; Nolta, Jan; Phinney, Donald G; Rocco, Patricia RM; Shi, Yufang; Tarte, Karin; Viswanathan, Sowmya; Martin, Ivan
Open Access
Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease.
(J Gene Med, 2010-11) Sun, Baodong; Li, Songtao; Bird, Andrew; Yi, Haiqing; Kemper, Alex; Thurberg, Beth L; Koeberl, Dwight D
BACKGROUND: Lysosomal storage disorders such as Pompe disease can be more effectively treated, if immune tolerance to enzyme or gene replacement therapy can be achieved. Alternatively, immune responses against acid α-glucosidase (GAA) might be evaded in Pompe disease through muscle-specific expression of GAA with adeno-associated virus (AAV) vectors. METHODS: An AAV vector containing the MHCK7 regulatory cassette to drive muscle-specific GAA expression was administered to GAA knockout (KO) mice, immune tolerant GAA-KO mice and mannose-6-phosphate deficient GAA-KO mice. GAA activity and glycogen content were analyzed in striated muscle to determine biochemical efficacy. RESULTS: The biochemical efficacy from GAA expression was slightly reduced in GAA-KO mice, as demonstrated by higher residual glycogen content in skeletal muscles. Next, immune tolerance to GAA was induced in GAA-KO mice by co-administration of a second AAV vector encoding liver-specific GAA along with the AAV vector encoding muscle-specific GAA. Antibody formation was prevented by liver-specific GAA, and the biochemical efficacy of GAA expression was improved in the absence of antibodies, as demonstrated by significantly reduced glycogen content in the diaphragm. Efficacy was reduced in old GAA-KO mice despite the absence of antibodies. The greatest impact upon gene therapy was observed in GAA-KO mice lacking the mannose-6-phosphate receptor in muscle. The clearance of stored glycogen was markedly impaired despite high GAA expression in receptor-deficient Pompe disease mice. CONCLUSIONS: Overall, antibody formation had a subtle effect upon efficacy, whereas the absence of mannose-6-phosphate receptors markedly impaired muscle-targeted gene therapy in murine Pompe disease.
Open Access
Enhancement of cardiac function after adenoviral-mediated in vivo intracoronary beta2-adrenergic receptor gene delivery.
(J Clin Invest, 1999-07) Maurice, JP; Hata, JA; Shah, AS; White, DC; McDonald, PH; Dolber, PC; Wilson, KH; Lefkowitz, RJ; Glower, DD; Koch, WJ
Exogenous gene delivery to alter the function of the heart is a potential novel therapeutic strategy for treatment of cardiovascular diseases such as heart failure (HF). Before gene therapy approaches to alter cardiac function can be realized, efficient and reproducible in vivo gene techniques must be established to efficiently transfer transgenes globally to the myocardium. We have been testing the hypothesis that genetic manipulation of the myocardial beta-adrenergic receptor (beta-AR) system, which is impaired in HF, can enhance cardiac function. We have delivered adenoviral transgenes, including the human beta2-AR (Adeno-beta2AR), to the myocardium of rabbits using an intracoronary approach. Catheter-mediated Adeno-beta2AR delivery produced diffuse multichamber myocardial expression, peaking 1 week after gene transfer. A total of 5 x 10(11) viral particles of Adeno-beta2AR reproducibly produced 5- to 10-fold beta-AR overexpression in the heart, which, at 7 and 21 days after delivery, resulted in increased in vivo hemodynamic function compared with control rabbits that received an empty adenovirus. Several physiological parameters, including dP/dtmax as a measure of contractility, were significantly enhanced basally and showed increased responsiveness to the beta-agonist isoproterenol. Our results demonstrate that global myocardial in vivo gene delivery is possible and that genetic manipulation of beta-AR density can result in enhanced cardiac performance. Thus, replacement of lost receptors seen in HF may represent novel inotropic therapy.
Open Access
Gene Therapy and Spinal Fusion: Systematic Review and Meta-Analysis of the Available Data.
(World neurosurgery, 2024-06) Cottrill, Ethan; Pennington, Zach; Sattah, Nathan; Jing, Crystal; Salven, Dave; Johnson, Eli; Downey, Max; Varghese, Shyni; Rocos, Brett; Richardson, William
Objective
To analyze the extant literature describing the application of gene therapy to spinal fusion.
Methods
A systematic review of the English-language literature was performed. The search query was designed to include all published studies examining gene therapy approaches to promote spinal fusion. Approaches were classified as ex vivo (delivery of genetically modified cells) or in vivo (delivery of growth factors via vectors). The primary endpoint was fusion rate. Random effects meta-analyses were performed to calculate the overall odds ratio (OR) of fusion using a gene therapy approach and overall fusion rate. Subgroup analyses of fusion rate were also performed for each gene therapy approach.
Results
Of 1179 results, 35 articles met criteria for inclusion (all preclinical), of which 26 utilized ex vivo approaches and 9 utilized in vivo approaches. Twenty-seven articles (431 animals) were included in the meta-analysis. Gene therapy use was associated with significantly higher fusion rates (OR 77; 95% confidence interval {CI}: [31, 192]; P < 0.001); ex vivo strategies had a greater effect (OR 136) relative to in vivo strategies (OR 18) (P = 0.017). The overall fusion rate using a gene therapy approach was 80% (95% CI: [62%, 93%]; P < 0.001); overall fusion rates were significantly higher in subjects treated with ex vivo compared to in vivo strategies (90% vs. 42%; P = 0.011). For both ex vivo and in vivo approaches, the effect of gene therapy on fusion was independent of animal model.
Conclusions
Gene therapy may augment spinal fusion; however, future investigation in clinical populations is necessary.
Open Access
Gene therapy for glycogen storage diseases.
(Human molecular genetics, 2019-10) Kishnani, Priya S; Sun, Baodong; Koeberl, Dwight D
The focus of this review is the development of gene therapy for glycogen storage diseases (GSDs). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body. Broadly, GSDs can be divided into types that affect liver or muscle or both tissues. For example, glucose-6-phosphatase (G6Pase) deficiency in GSD type Ia (GSD Ia) affects primarily the liver and kidney, while acid α-glucosidase (GAA) deficiency in GSD II causes primarily muscle disease. The lack of specific therapy for the GSDs has driven efforts to develop new therapies for these conditions. Gene therapy needs to replace deficient enzymes in target tissues, which has guided the planning of gene therapy experiments. Gene therapy with adeno-associated virus (AAV) vectors has demonstrated appropriate tropism for target tissues, including the liver, heart and skeletal muscle in animal models for GSD. AAV vectors transduced liver and kidney in GSD Ia and striated muscle in GSD II mice to replace the deficient enzyme in each disease. Gene therapy has been advanced to early phase clinical trials for the replacement of G6Pase in GSD Ia and GAA in GSD II (Pompe disease). Other GSDs have been treated in proof-of-concept studies, including GSD III, IV and V. The future of gene therapy appears promising for the GSDs, promising to provide more efficacious therapy for these disorders in the foreseeable future.
Open Access
Gene therapy offers new hope for children with metachromatic leukodystrophy.
(Lancet (London, England), 2022-01) Kurtzberg, Joanne
Open Access
Hydrostatic isolated limb perfusion with adeno-associated virus vectors enhances correction of skeletal muscle in Pompe disease.
(Gene Ther, 2010-12) Sun, B; Li, S; Bird, A; Koeberl, DD
Glycogen storage disease type II (Pompe disease; MIM 232300) stems from the inherited deficiency of acid-α-glucosidase (GAA; acid maltase; EC 3.2.1.20), which primarily involves cardiac and skeletal muscles. We hypothesized that hydrostatic isolated limb perfusion (ILP) administration of an adeno-associated virus (AAV) vector containing a muscle-specific promoter could achieve relatively higher transgene expression in the hindlimb muscles of GAA-knockout (GAA-KO) mice, in comparison with intravenous (IV) administration. ILP administration of AAV2/8 vectors encoding alkaline phosphatase or human GAA-transduced skeletal muscles of the hindlimb widely, despite the relatively low number of vector particles administered (1 × 10¹¹), and IV administration of an equivalent vector dose failed to transduce skeletal muscle detectably. Similarly, ILP administration of fewer vector particles of the AAV2/9 vector encoding human GAA (3 × 10¹⁰) transduced skeletal muscles of the hindlimb widely and significantly reduced glycogen content to, in comparison with IV administration. The only advantage for IV administration was moderately high-level transduction of cardiac muscle, which demonstrated compellingly that ILP administration sequestered vector particles within the perfused limb. Reduction of glycogen storage in the extensor digitorum longus demonstrated the potential advantage of ILP-mediated delivery of AAV vectors in Pompe disease, because type II myofibers are resistant to enzyme replacement therapy. Thus, ILP will enhance AAV transduction of multiple skeletal muscles while reducing the required dosages in terms of vector particle numbers.
Open Access
Identifying Treatments for Taste and Smell Disorders: Gaps and Opportunities.
(Chemical senses, 2020-10) Mainland, Joel D; Barlow, Linda A; Munger, Steven D; Millar, Sarah E; Vergara, M Natalia; Jiang, Peihua; Schwob, James E; Goldstein, Bradley J; Boye, Shannon E; Martens, Jeffrey R; Leopold, Donald A; Bartoshuk, Linda M; Doty, Richard L; Hummel, Thomas; Pinto, Jayant M; Trimmer, Casey; Kelly, Christine; Pribitkin, Edmund A; Reed, Danielle R
The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the "Identifying Treatments for Taste and Smell Disorders" conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders.
Open Access
Immunodominant liver-specific expression suppresses transgene-directed immune responses in murine pompe disease.
(Hum Gene Ther, 2012-05) Zhang, P; Sun, B; Osada, T; Rodriguiz, R; Yang, XY; Luo, X; Kemper, AR; Clay, TM; Koeberl, DD
Pompe disease can be treated effectively, if immune tolerance to enzyme replacement therapy (ERT) with acid α-glucosidase (GAA) is present. An adeno-associated viral (AAV) vector carrying a liver-specific regulatory cassette to drive GAA expression (AAV-LSPhGAA) established immune tolerance in GAA knockout (KO) mice, whereas ubiquitous expression with AAV-CBhGAA provoked immune responses. Therefore, we investigated the hypothesis that immune tolerance induced by hepatic-restricted expression was dominant. AAV-LSPhGAA and AAV-CBhGAA were administered singly or in combination to groups of adult GAA-KO mice, and AAV-LSPhGAA induced immune tolerance even in combination with AAV-CBhGAA. The dual vector approach to GAA expression improved biochemical correction of GAA deficiency and glycogen accumulations at 18 weeks, and improved motor function testing including wire-hang and grip-strength testing. The greatest efficacy was demonstrated by dual vector administration, when both vectors were pseudotyped as AAV8. T cells from mice injected with AAV-LSPhGAA failed to proliferate at all after an immune challenge with GAA and adjuvant, whereas mock-treated GAA-KO mice mounted vigorous T cell proliferation. Unlike AAV-LSPhGAA, AAV-CBhGAA induced selective cytokine and chemokine expression in liver and spleen after the immune challenge. AAV-CBhGAA transduced dendritic cells and expressed high-level GAA, whereas AAV-LSPhGAA failed to express GAA in dendritic cells. The level of transduction in liver was much higher after dual AAV8 vector administration at 18 weeks, in comparison with either vector alone. Dual vector administration failed to provoke antibody formation in response to GAA expression with AAV-CBhGAA; however, hepatic-restricted expression from dual vector expression did not prevent antibody formation after a strong immune challenge with GAA and adjuvant. The relevance of immune tolerance to gene therapy in Pompe disease indicates that hepatic expression might best be combined with nonhepatic expression, achieving the benefits of ubiquitous expression in addition to evading deleterious immune responses.
Open Access
Intracoronary adenovirus-mediated delivery and overexpression of the beta(2)-adrenergic receptor in the heart : prospects for molecular ventricular assistance.
(Circulation, 2000-02-01) Glower, Donald D Jr; Hata, Jonathan Andrew; Koch, Walter J; Kypson, Alan P; Lefkowitz, Robert J; Lilly, R Eric; Pippen, Anne; Shah, AS; Silvestry, Scott Christopher; Tai, Oliver
BACKGROUND: Genetic modulation of ventricular function may offer a novel therapeutic strategy for patients with congestive heart failure. Myocardial overexpression of beta(2)-adrenergic receptors (beta(2)ARs) has been shown to enhance contractility in transgenic mice and reverse signaling abnormalities found in failing cardiomyocytes in culture. In this study, we sought to determine the feasibility and in vivo consequences of delivering an adenovirus containing the human beta(2)AR cDNA to ventricular myocardium via catheter-mediated subselective intracoronary delivery. METHODS AND RESULTS: Rabbits underwent percutaneous subselective catheterization of either the left or right coronary artery and infusion of adenoviral vectors containing either a marker transgene (Adeno-betaGal) or the beta(2)AR (Adeno-beta(2)AR). Ventricular function was assessed before catheterization and 3 to 6 days after gene delivery. Both left circumflex- and right coronary artery-mediated delivery of Adeno-beta(2)AR resulted in approximately 10-fold overexpression in a chamber-specific manner. Delivery of Adeno-betaGal did not alter in vivo left ventricular (LV) systolic function, whereas overexpression of beta(2)ARs in the LV improved global LV contractility, as measured by dP/dt(max), at baseline and in response to isoproterenol at both 3 and 6 days after gene delivery. CONCLUSIONS: Percutaneous adenovirus-mediated intracoronary delivery of a potentially therapeutic transgene is feasible, and acute global LV function can be enhanced by LV-specific overexpression of the beta(2)AR. Thus, genetic modulation to enhance the function of the heart may represent a novel therapeutic strategy for congestive heart failure and can be viewed as molecular ventricular assistance.
Open Access
Intrastromal Gene Therapy Prevents and Reverses Advanced Corneal Clouding in a Canine Model of Mucopolysaccharidosis I.
(Molecular therapy : the journal of the American Society of Gene Therapy, 2020-06) Miyadera, Keiko; Conatser, Laura; Llanga, Telmo A; Carlin, Kendall; O'Donnell, Patricia; Bagel, Jessica; Song, Liujiang; Kurtzberg, Joanne; Samulski, R Jude; Gilger, Brian; Hirsch, Matthew L
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disease characterized by severe phenotypes, including corneal clouding. MPS I is caused by mutations in alpha-l-iduronidase (IDUA), a ubiquitous enzyme that catalyzes the hydrolysis of glycosaminoglycans. Currently, no treatment exists to address MPS I corneal clouding other than corneal transplantation, which is complicated by a high risk for rejection. Investigation of an adeno-associated virus (AAV) IDUA gene addition strategy targeting the corneal stroma addresses this deficiency. In MPS I canines with early or advanced corneal disease, a single intrastromal AAV8G9-IDUA injection was well tolerated at all administered doses. The eyes with advanced disease demonstrated resolution of corneal clouding as early as 1 week post-injection, followed by sustained corneal transparency until the experimental endpoint of 25 weeks. AAV8G9-IDUA injection in the MPS I canine eye with early corneal disease prevented the development of advanced corneal changes while restoring clarity. Biodistribution studies demonstrated vector genomes in ocular compartments other than the cornea and in some systemic organs; however, a capsid antibody response was detected in only the highest dosed subject. Collectively, the results suggest that intrastromal AAV8G9-IDUA therapy prevents and reverses visual impairment associated with MPS I corneal clouding.
Open Access
Opioid Self-Administration is Attenuated by Early-Life Experience and Gene Therapy for Anti-Inflammatory IL-10 in the Nucleus Accumbens of Male Rats.
(Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2017-10) Lacagnina, Michael J; Kopec, Ashley M; Cox, Stewart S; Hanamsagar, Richa; Wells, Corinne; Slade, Susan; Grace, Peter M; Watkins, Linda R; Levin, Edward D; Bilbo, Staci D
Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation, and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). We thus hypothesized that anti-inflammatory signaling may underlie the effects of early-life experience on later-life opioid drug-taking. Here we demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug-concentration-dependent manner. Transcriptional profiling of the nucleus accumbens (NAc) from handled rats following repeated exposure to remifentanil reveals a suppression of pro-inflammatory cytokine and chemokine gene expression, consistent with an anti-inflammatory phenotype. To determine if anti-inflammatory signaling alters drug-taking behavior, we administered intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We discovered that pDNA-IL-10 treatment reduces remifentanil self-administration in a drug-concentration-dependent manner, similar to the effect of handling. In contrast, neither handling nor pDNA-IL-10 treatment alters self-administration of food or sucrose rewards. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs. Moreover, manipulation of the IL-10 signaling pathway represents a novel approach for influencing opioid reinforcement.
Open Access
Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury.
(Circ Res, 1999-11-26) Cross, HR; Steenbergen, C; Lefkowitz, RJ; Koch, WJ; Murphy, E
Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of beta(2)AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because beta(2)ARs, unlike beta(1)ARs, couple to G(i) as well as G(s), we pretreated mice with the G(i) inhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGbetaARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGbetaARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, beta(2)AR overexpression increased ischemic injury, whereas betaARK1 overexpression was protective. Ischemic injury in the beta(2)AR overexpressors was exacerbated by PTX treatment, implying that it was G(s) not G(i) activity that enhanced injury. Unlike beta(2)AR overexpression, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.
Open Access
Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia.
(Molecular Genetics and Metabolism, 2013-06) Brooks, Elizabeth Drake; Little, Dianne; Arumugam, Ramamani; Sun, Baodong; Curtis, Sarah; Demaster, Amanda; Maranzano, Michael; Jackson, Mark W; Kishnani, Priya; Freemark, Michael S; Koeberl, Dwight D
Glycogen Storage Disease type Ia (GSD-Ia) in humans frequently causes delayed bone maturation, decrease in final adult height, and decreased growth velocity. This study evaluates the pathogenesis of growth failure and the effect of gene therapy on growth in GSD-Ia affected dogs and mice. Here we found that homozygous G6pase (-/-) mice with GSD-Ia have normal growth hormone (GH) levels in response to hypoglycemia, decreased insulin-like growth factor (IGF) 1 levels, and attenuated weight gain following administration of GH. Expression of hepatic GH receptor and IGF 1 mRNAs and hepatic STAT5 (phospho Y694) protein levels are reduced prior to and after GH administration, indicating GH resistance. However, restoration of G6Pase expression in the liver by treatment with adeno-associated virus 8 pseudotyped vector expressing G6Pase (AAV2/8-G6Pase) corrected body weight, but failed to normalize plasma IGF 1 in G6pase (-/-) mice. Untreated G6pase (-/-) mice also demonstrated severe delay of growth plate ossification at 12 days of age; those treated with AAV2/8-G6Pase at 14 days of age demonstrated skeletal dysplasia and limb shortening when analyzed radiographically at 6 months of age, in spite of apparent metabolic correction. Moreover, gene therapy with AAV2/9-G6Pase only partially corrected growth in GSD-Ia affected dogs as detected by weight and bone measurements and serum IGF 1 concentrations were persistently low in treated dogs. We also found that heterozygous GSD-Ia carrier dogs had decreased serum IGF 1, adult body weights and bone dimensions compared to wild-type littermates. In sum, these findings suggest that growth failure in GSD-Ia results, at least in part, from hepatic GH resistance. In addition, gene therapy improved growth in addition to promoting long-term survival in dogs and mice with GSD-Ia.
Open Access
Preclinical Development of New Therapy for Glycogen Storage Diseases.
(Curr Gene Ther, 2015) Sun, Baodong; Brooks, Elizabeth D; Koeberl, Dwight D
Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available.
Open Access
Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.
(Proc Natl Acad Sci U S A, 2000-05-09) White, DC; Hata, JA; Shah, AS; Glower, DD; Lefkowitz, RJ; Koch, WJ
When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are mediated through enhanced activity of the betaAR kinase (betaARK1), the expression of which is increased in ischemic and failing myocardium. These changes are widely viewed as representing an adaptive mechanism, which protects the heart against chronic activation. In this study, we demonstrate, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of betaARK1 (betaARKct), that the desensitization and down-regulation of betaARs seen in the failing heart may actually be maladaptive. In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical betaAR abnormalities seen in human heart failure, delivery of the betaARKct transgene at the time of myocardial infarction prevents the rise in betaARK1 activity and expression and thereby maintains betaAR density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of betaAR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of betaARK1 and preservation of myocardial betaAR function.
Open Access
Salmeterol enhances the cardiac response to gene therapy in Pompe disease.
(Mol Genet Metab, 2016-05) Han, Sang-Oh; Li, Songtao; Koeberl, Dwight D
Enzyme replacement therapy (ERT) with recombinant human (rh) acid α-glucosidase (GAA) has prolonged the survival of patients. However, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up rhGAA, correlated with a poor response to ERT by muscle in Pompe disease. Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through Igf-1 mediated muscle hypertrophy, which correlated with increased CI-MPR (also the Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and dehydroepiandrosterone (DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing glycogen storage from the heart. Heart GAA activity was significantly increased by either salmeterol (p<0.01) or DHEA (p<0.05), in comparison with untreated mice. Furthermore, glycogen content was reduced in the heart by treatment with DHEA (p<0.001), salmeterol (p<0.05), formoterol (p<0.01), or clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that salmeterol and the AAV vector significantly increased performance, in comparison with the AAV vector alone (p<0.001). Similarly, salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus, salmeterol should be further developed as adjunctive therapy in combination with either ERT or gene therapy for Pompe disease.
Open Access
Standardization, workforce development and advocacy in cell and gene therapies: a summary of the 2020 Regenerative Medicine InterCHANGE.
(Cytotherapy, 2021-10) McNiece, Ian K; Wacker, Kara K; Kurtzberg, Joanne; Warkentin, Phyllis I
Cell and gene therapy is a promising and disruptive new field of medicine for diseases lacking effective treatments. Collaboration among stakeholders has become critically important as investigators, health care providers, manufacturers, couriers, data registries, regulators and payers all become more invested in the success of this field. Many organizations have collaborated with each other to increase clarity, advocate for improvements and share lessons learned. These efforts appear to be making an impact, although the potential for duplicative efforts could slow progress. The second Regenerative Medicine InterCHANGE, hosted by the Foundation for the Accreditation of Cellular Therapy, took place at the Phacilitate Leaders World/World Stem Cell Summit conference in Miami, Florida, on January 24, 2020. Participants from several organizations outlined needs to advance cell and gene therapies. Efforts to address these include standardization, workforce development and advocacy. This article summarizes the major challenges and opportunities discussed during the InterCHANGE.

Browsing by Subject "Genetic Therapy"

Objective

Methods

Results

Conclusions