Before an experimental treatment can be tested on human subjects in a clinical trial, it must have shown benefit in laboratory testing or animal research studies. The most promising treatments are then moved into clinical trials, with the goal of identifying new ways to safely and effectively prevent, screen for, diagnose, or treat a disease.

Speak with your doctor about the ongoing progress and results of these trials to get the most up-to-date information on new treatments. Participating in a clinical trial is a great way to contribute to curing, preventing and treating liver disease and its complications.

Start your search here to find clinical trials that need people like you. Glycogen Storage Disease Type 1 von Gierke. What is Liver Disease? How Many People Have Liver Disease?

Facts at-a-Glance Also known as von Gierke disease , is a more severe form of Glycogen Storage Disease. All Glycogen Storage diseases together affect fewer than 1 in 40, persons in the United States.

Information for the Newly Diagnosed What are the symptoms of GSD I? What causes GSD I? How is GSD I diagnosed? How is GSD I treated? Who is at risk for GSD I? Frequent feedings of uncooked cornstarch are used to maintain and improve blood levels of glucose.

Allopurinol, a drug capable of reducing the level of uric acid in the blood, may be useful to control the symptoms of gout-like arthritis during the adolescent years.

Human granulocyte colony stimulating factor GCSF may be used to treat recurrent infections in GSD type Ib patients. Liver tumors adenomas can be treated with minor surgery or a procedure in which adenomas are ablated using heat and current radiofrequency ablation.

Individuals with GSDI should be monitored at least annually with kidney and liver ultrasound and routine blood work specifically used for monitoring GSD patients.

Information on current clinical trials is posted on the Internet at www. All studies receiving U. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the National Institutes of Health NIH in Bethesda, MD, contact the NIH Patient Recruitment Office:. Tollfree: TTY: Email: prpl cc. For information about clinical trials sponsored by private sources, contact: www.

TEXTBOOKS Chen YT, Bali DS. Prenatal Diagnosis of Disorders of Carbohydrate Metabolism. In: Milunsky A, Milunsky J, eds. Genetic disorders and the fetus — diagnosis, prevention, and treatment. West Sussex, UK: Wiley-Blackwell; Chen Y.

Glycogen storage disease and other inherited disorders of carbohydrate metabolism. In: Kasper DL, Braunwald E, Fauci A, et al. New York, NY: McGraw-Hill; Weinstein DA, Koeberl DD, Wolfsdorf JI.

Type I Glycogen Storage Disease. In: NORD Guide to Rare Disorders. Philadelphia, PA: Lippincott, Williams and Wilkins; JOURNAL ARTICLES Chou JY, Jun HS, Mansfield BC. J Inherit Metab Dis. doi: Epub Oct 7. PubMed PMID: Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D, Somers MJ, Wechsler SB, Weinstein DA, Wolfsdorf JI, Watson MS; American College of Medical Genetics and Genomics.

Genet Med. Austin SL, El-Gharbawy AH, Kasturi VG, James A, Kishnani PS. Menorrhagia in patients with type I glycogen storage disease.

Obstet Gynecol ;— Dagli AI, Lee PJ, Correia CE, et al. Pregnancy in glycogen storage disease type Ib: gestational care and report of first successful deliveries. Chou JY, Mansfield BC. Mutations in the glucosephosphatase-alpha G6PC gene that cause type Ia glycogen storage disease.

Hum Mutat. Franco LM, Krishnamurthy V, Bali D, et al. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

Lewis R, Scrutton M, Lee P, Standen GR, Murphy DJ. Antenatal and Intrapartum care of a pregnant woman with glycogen storage disease type 1a. Eur J Obstet Gynecol Reprod Biol. Ekstein J, Rubin BY, Anderson, et al.

Mutation frequencies for glycogen storage disease in the Ashkenazi Jewish Population. Am J Med Genet A. Melis D, Parenti G, Della Casa R, et al.

Brain Damage in glycogen storage disease type I. J Pediatr. Rake JP, Visser G, Labrune, et al. Guidelines for management of glycogen storage disease type I-European study on glycogen storage disease type I ESGSD I.

Eur J Pediatr. Rake JP Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I EGGSD I. Eur J Pediat. Chou JY, Matern D, Mansfield, et al.

Type I glycogen Storage diseases: disorders of the glucosePhosphatase complex. Curr Mol Med. Schwahn B, Rauch F, Wendel U, Schonau E. Additionally, as patients with IPD are surviving well into adolescence, and patients with LOPD are being identified earlier through diagnostic advancements such as newborn screening 15 , a new natural history is revealing persistent manifestations of the disease despite treatment with ERT 16 , For example, one limitation is the insufficient or lack of glycogen clearance in certain tissue types, such as smooth muscle across vascular, ocular, gastrointestinal and respiratory systems Reports have also revealed white matter lesions in the brain, which was previously thought to remain unaffected in Pompe disease 19 , Although some of these challenges can be resolved to a certain extent through close disease monitoring, adjunctive therapies to ERT and a multi-systemic approach to care, there is a demonstrated need for new therapies that can successfully target these specific manifestations.

Adeno-associated virus AAV vectors will express G6Pase in the liver, improving the abnormalities of GSD Ia. AAV vector administration to young mice accomplished a high level of liver transduction Fig. This phenomenon reflected the episomal nature of AAV vector genomes that are lost as cells divide during growth and development.

Similarly, an rAAV8 vector was administered to a GSD Ia puppy at one day of age and prevented hypoglycemia for 3 h at 1 month of age; however, by 2 months of age the dog became hypoglycemic after 1 h of fasting and retreatment with a new rAAV1 vector was needed to restore efficacy A larger study demonstrated greatly prolonged survival in GSD Ia dogs following treatment with repeated AAV vector administration using a new serotype for each treatment; however, those vectors failed to prevent progression of liver or kidney involvement from GSD Ia 25 , Integrating AAV vectors have been developed for the treatment of GSD Ia The AAV-ZFN vector safely generated DNA breaks in the ROSA26 gene, which allowed integration of the AAV-G6Pase vector by homologous recombination to integrate the G6PC -derived transgene.

Without the ZFN, integration occurs at random breaks in chromosomal DNA at a lower rate Treatment with the peroxisome proliferator-activated receptor PPAR -agonist bezafibrate in GSD Ia mice lowered glycogen and triglycerides in liver Therefore, we tested whether bezafibrate would enhance the efficiency of ZFN-mediated gene editing 27 by normalizing autophagy in the GSD Ia liver Bezafibrate with gene editing decreased liver glycogen and increased G6Pase activity and prevented hypoglycemia during fasting.

Furthermore, bezafibrate-treated mice had a higher number of vector genomes, and ZFN activity was higher. Bezafibrate treatment normalized the impaired molecular signaling in GSD Ia as follows: 1 the expression of PPARα, a master regulator of fatty acid β-oxidation; and 2 the expression of PPARγ, a lipid regulator signaling.

Therefore, bezafibrate improved the hepatic environment and increased the transduction efficiency of AAV vectors in liver, while higher expression of G6Pase corrected molecular signaling in GSD Ia.

Thus, the benefits from stimulating autophagy during gene editing were two-fold: 1 from reversing the hepatosteatosis of GSD Ia 31 , and 2 from increasing AAV vector transduction The prevention of HCA and HCC were described by Lee et al. The treated mice displayed normal hepatic triglyceride content, had normal blood glucose in response to a glucose tolerance test, had decreased fasting blood insulin levels and maintained normoglycemia over a 24 h fast.

A comparison between AAV-PE with another rAAV8 vector containing a minimal G6PC promoter sequence AAV-G6Pase 34 revealed higher transgene expression from the large G6PC promoter sequence in AAV-GPE The high-level G6Pase activity achieved with AAV-GPE might explain the remarkably high efficacy achieved from only few cells expressing G6PC in the liver.

Kim et al. Given the success of gene therapy with AAV-GPE, a Phase I clinical trial is currently underway with that vector NCT GSD Ib is complicated by neutropenia associated with increased risk for infection and related to the deficiency of glucosephosphate transporter G6PT , in addition to the liver and kidney involvement characteristic of GSD I This myeloid dysfunction has resisted AAV vector transduction, which is readily understood related to the episomal status of AAV vector genomes that leads to loss of vector genomes during cell division Consistent with this prediction, AAV vector-mediated gene therapy has reversed hepatic involvement and hypoglycemia when transduction was sufficient.

Neutropenia persisted despite the reversal of biochemical abnormalities in these mice with GSD Ib, which suggested that episomal AAV vector genomes containing G6PT were lost from rapidly dividing neutrophils. Amalfitano et al. demonstrated that high-level liver expression from a modified adenovirus vector produced circulating GAA in the blood, accompanied by receptor-mediated uptake in the heart and skeletal muscle Although the GAA expression for liver proved to be transient, adenovirus vector-mediated GAA expression from the liver depot achieved high-level biochemical correction throughout the heart and skeletal muscle Adenovirus vector-mediated gene therapy provoked anti-GAA antibodies that interfered with the biochemical correction of muscle However, anti-GAA antibodies could be reduced by including a liver-specific regulatory cassette to drive GAA expression Overall, these studies confirmed high-level production of GAA in the blood corrected the heart and skeletal muscle through cation-independent mannose 6-phoshate receptor CI-MPR mediated uptake of precursor GAA and trafficking to the lysosomes, where GAA was processed and cleared stored glycogen.

More recently AAV vectors have developed to produce secreted proteins including coagulation factors and lysosomal enzymes 45—47 , including GAA in Pompe disease The potential for liver depot gene therapy with AAV vectors to surpass ERT was demonstrated by studies that corrected GAA deficiency Fig.

Importantly, liver depot gene therapy can correct type II myofiber muscles that resist correction from ERT 49 , Later studies suggested the feasibility of clearing sequestered glycogen from the central nervous system CNS following high-level hepatic GAA production 51 , 52 , which can be attributed to CI-MPR-mediated transfer of a lysosomal enzyme such as GAA across the blood—brain barrier One advantage of gene therapy over ERT stems from the continuous, low-level exposure of skeletal muscle to GAA from the liver depot, in contrast to periodic, high-level exposure from ERT The concept of AAV vector-mediated liver-specific transgene expression to suppress antibody responses against therapeutic proteins was developed first in animal models for hemophilia 55 , 56 and later in Fabry disease 47 and Pompe disease 48 , Immune tolerance to GAA was induced by liver-specific expression, which was confirmed by the absence of anti-GAA antibody formation following vector administration 57— Furthermore, low-dose AAV vector administration could induce immune tolerance to GAA that enhanced the efficacy from simultaneous ERT 57 , The induction of immune tolerance to GAA improved the biochemical correction from simultaneous ERT and prevented hypersensitivity reactions by suppressing anti-GAA antibody formation.

The underlying mechanism is the activation of regulatory T cells that suppress antibody responses against GAA latter, which has been termed immunomodulatory gene therapy The high tropism of AAV vectors for the liver reduces the dose requirements for gene therapy in Pompe disease.

Muscle-targeted gene therapy has been attempted by incorporating a highly active muscle-specific regulatory cassette MHCK7 in an AAV vector encoding GAA 62 , but dose requirements were high. Intriguingly, these immune responses against systemic GAA expression with a constitutive promoter can be suppressed by simultaneous administration of an AAV vector containing a liver-specific promoter to induce immune tolerance to GAA 59 , Gene therapy can be enhanced by methods to increase GAA secretion from the liver or to increase CI-MPR expression in skeletal muscle.

The initial study of enhancing secretion of GAA modified the signal peptide of GAA to one from a highly secreted protein to produce a chimeric, secreted GAA 65 , High-level hGAA was sustained in the plasma of mice with Pompe disease for 24 weeks following administration of an rAAV8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain These data confirmed the feasibility of modifying GAA to drive secretion from transduced hepatocytes, thereby increasing the availability of GAA for the cross-correction of skeletal muscle.

A more recent study of chimeric GAA confirmed the strategy of modifying the signal peptide Another vector containing GAA that combined both modifications of altering the signal peptide and codon-optimization successfully avoided anti-GAA formation at those dosages.

These initial studies suggested that efficacy can be increased from a chimeric, codon-optimized GAA, if immune tolerance to GAA can be achieved. Another strategy to enhance gene therapy in Pompe disease consists of inducing expression of CI-MPR in skeletal muscle 50 , Treatment with the long-acting, selective β2-agonist clenbuterol increased CI-MPR in skeletal muscle and in the brain.

The efficacy of liver depot gene therapy was enhanced by the addition of clenbuterol, as demonstrated by increased rotarod latency, in comparison with vector alone.

Glycogen content was lower in skeletal muscles following combination therapy, including the tibialis anterior containing mainly type II myofibers, in comparison with vector treatment alone Consistent with this preclinical data, a Phase I clinical trial revealed improved muscle function and biochemical correction following clenbuterol treatment in addition to ERT, in comparison with ERT alone, for adult patients with Pompe disease Lim et al.

recently reported that an rAAVPHP. The rAAVPHP. B vector containing human GAA under the control of the CB promoter produced widespread GAA at supraphysiologic concentrations in the brain and heart, and glycogen content was significantly decreased in the brain, heart and skeletal muscle following vector administration.

This biochemical correction correlated with the normalization of neuromuscular function. Although the rAAVPHP.

B vector would not transduce human tissues and would not be effective in a clinical trial, this proof-of-concept data demonstrated the unprecedented reversal of muscle and nerve involvement with an AAV vector A Phase I clinical trial of liver depot gene therapy for Pompe disease has begun enrolling adult patients NCT This study will evaluate an rAAV8 vector containing a liver-specific promoter to drive wild-type GAA expression.

Rather than frequent infusions of a recombinant protein, as in ERT, gene therapy with an rAAV8 vector will be performed once with long-lasting effects.

Given proof-of-concept studies, it is anticipated that this strategy will induce specific immune tolerance to GAA in Pompe disease with a low dosage of this rAAV8 vector that expresses GAA only in liver, rAAV8 -LSPhGAA 57 , This preclinical data justified a starting dose of 1.

The first cohort of patients has been enrolled in this ongoing study. Recombinant AAV vectors are currently preferred vehicles for the delivery of gene expression cassettes for their favorable safety properties and robust transduction capabilities.

Despite the rapid advances in gene therapy for GSD I and GSD II in the past decades, limited studies have been reported for other GSDs. Mutations in the AGL gene cause genetic deficiency of GDE, resulting in excessive accumulation of glycogen with short outer branches limit dextrin in multiple tissues, predominantly in liver and muscle.

Progressive hepatic cirrhosis and liver failure can occur with age Table 1 ; hepatic adenomas and hepatocellular carcinoma have been reported in some cases 6 , 70— Muscle weakness is present during childhood, and progressive myopathy and cardiomyopathy are major causes of morbidity in adults 6 , 73— A major hurdle toward developing AAV-mediated gene therapy for GSD III is the inability to package a gene expression cassette containing the large-sized 4.

To overcome this limitation, Vidal et al. The two vectors share an overlap sequence for homologous recombination of the two segments to form the full-length hGDE coding sequence in vivo. Substitution of the hAAT vector with the universal CMV promoter resulted in hGDE expression and glycogen reduction in the heart and skeletal muscles, but not in the liver, likely due to the inactivation of the CMV promoter in the liver.

The use of a liver-active CMV enhancer chicken beta-actin promoter in the dual vectors improved liver correction and rescued muscle function While promising, a major limitation of this approach is that a cell has to acquire both vectors by a high-dose vector administration and then rely on the low-efficiency reconstitution of the full-length hGDE cDNA through homologous recombination, which cannot achieve an efficiency comparable to a single vector system.

In the same article, the authors also reported that administration of an AAV vector expressing a secreted form of human GAA Pompe disease significantly decreased glycogen accumulation in the liver, but this treatment failed to rescue glycemia and muscle function in GSD IIIa mice Recently Pursell et al.

GSD IV is caused by the deficiency of GBE and characterized by the accumulation of a poorly soluble, amylopectin-like glycogen polyglucosan bodies in liver, muscle and the CNS 78— Liver transplantation is the only treatment optional for GSD IV. Recently Yi et al. reported a gene therapy study in a mouse model of adult form of GSD IV At 3 months of age, GBE enzyme activity was highly elevated in heart, and significantly increased in skeletal muscles and the brain, but not in liver of the AAV-treated mice.

Glycogen contents were reduced to wild-type levels in skeletal muscles and significantly decreased in the liver and brain Plasma biochemistry tests revealed an overall trend of decreased plasma enzyme activities of ALT, AST and CK at 9 months of age, suggesting an alleviation of damage in the liver and muscle from the AAV-GBE treatment However, the same AAV treatment failed to achieve efficacy when mice were treated at an adult age 3 months; unpublished data , which was likely a result of cytotoxic T cell immune responses provoked by the transgene expression human GBE.

Currently, we are evaluating strategies to suppress or evade cellular immune responses during gene therapy in adult mice. GSD V, also known as McArdle disease, is caused by mutations in the PYGM that encodes for the muscle form glycogen phosphorylase myophosphorylase enzyme Table 1.

Patients are frequently detected in the second to third decade of life by exercise intolerance with muscle cramping accompanied by elevated serum creatine kinase 85— There is no effective treatment for this disease, but many patients are able to perform moderate, sustained exercise on a carbohydrate-rich diet with carbohydrate ingestion shortly before exercise 89 , To date, the only gene therapy study for the disease was conducted in an ovine GSD V model Intramuscular injection of a modified adenovirus 5 or an AAV2 vector containing myophosphorylase expression cassettes under the control of a Rous Sarcoma virus or CMV promoter effectively transduced and expressed functional myophosphorylase in the muscle of GSD V sheep, but the activity of myophosphorylase waned over time in all the treated muscles Liver-targeted gene therapy with rAAV8 vectors has efficaciously corrected the glycogen storage of GSD Ia and Pompe disease in preclinical studies Fig.

Proof-of-concept experiments have successfully reversed the effects of GSD in multiple animal models, although further optimization will be required to advance gene therapy to clinical trials for GSDs other than GSD Ia and Pompe disease.

However, successful clinical trials in one or more GSDs will fuel optimism regarding the potential of gene therapy to treat many or all of the GSDs. National Institute of Diabetes and Digestive and Kidney Diseases R01DKA1 to D. Chen Center for Genetics and Genomics to D. has served on a data and safety monitoring board for Baxter International, and he has received funding from Roivant Rare Diseases.

received an honorarium and grant support in the past from Sanofi Genzyme and Amicus Therapeutics. and Duke University have equity in Asklepios Biopharmaceutical, Inc. AskBio , which is developing gene therapy for Pompe disease.

Additionally, P. and D. have developed technology that is described herein. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. We would like to acknowledge inspiration and support from Dr Emory and Mrs Mary.

Chapman and their son Christopher, and from Dr. John and Mrs. Michelle Kelly. We deeply appreciate the dedication shown by the staff of the Duke Department of Laboratory Animal Resources, as well as undergraduate students at the Duke University. Bali , D. and Goldstein , J. and Amemiya , A.

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