Gene Therapy for Glycogen Storage Disease Type Ia

Recruiting at 32 trial locations

Overseen By Grania Crowley

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Ultragenyx Pharmaceutical Inc

Must be taking: Cornstarch

Disqualifiers: Liver disease, Liver transplant, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

49 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests DTX401, a treatment to help people with a genetic condition called GSDIa manage their blood sugar levels better. It targets patients aged 8 and older who struggle to maintain normal blood sugar. The treatment aims to reduce the need for extra glucose by helping the body control blood sugar more effectively.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be on a stable regimen of cornstarch or equivalent for glucose control.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants should be on a stable regimen of cornstarch or equivalent, so you may need to continue that treatment.

What data supports the idea that Gene Therapy for Glycogen Storage Disease Type Ia is an effective treatment?

The available research shows that gene therapy using adeno-associated virus (AAV) vectors can significantly improve the condition of animals with Glycogen Storage Disease Type Ia. In studies with dogs, the therapy helped maintain normal blood sugar levels and reduced liver glycogen, which is a key problem in this disease. In one study, a dog treated with the therapy was able to stop dietary glucose supplements and continued to thrive with minimal issues for 18 months. Another study showed that the therapy corrected low blood sugar during fasting and improved liver function in both mice and dogs. These results suggest that gene therapy could be a promising alternative to current treatments, which mainly focus on managing symptoms rather than addressing the root cause of the disease. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment for Glycogen Storage Disease Type Ia?

Research shows that using adeno-associated virus (AAV) vectors in dogs with Glycogen Storage Disease Type Ia improved blood sugar levels and reduced liver glycogen, indicating that this gene therapy could be a promising treatment for the disease. ^{1 2 3 4 5}

What safety data is available for gene therapy in treating Glycogen Storage Disease Type Ia?

The safety data for gene therapy using adeno-associated virus (AAV) vectors, specifically AAV2/8, shows promising results in preclinical studies. In a canine model of Glycogen Storage Disease Type Ia, AAV2/8 vector delivery demonstrated significant correction of the disease phenotype with minimal laboratory abnormalities observed up to 18 months post-treatment. Additionally, studies on other diseases using AAV8 vectors, such as Pompe disease, reported no significant short- or long-term toxicity, although some immune responses were noted. However, systemic AAV administration can potentially trigger inflammatory responses, including thrombotic microangiopathy, depending on anti-capsid antibodies. Overall, while AAV-based gene therapy shows potential, careful consideration of immune responses and dose limits is necessary. ^{1 6 7 8 9}

Is gene therapy using AAV vectors generally safe in humans?

Gene therapy using AAV vectors has been shown to be generally safe in various studies, with some reports of mild and transient side effects like increased liver enzymes and localized immune responses. However, systemic administration can sometimes lead to serious inflammatory responses, so careful monitoring is necessary. ^{1 6 7 8 9}

Is the treatment DTX401 a promising treatment for Glycogen Storage Disease Type Ia?

Yes, DTX401 is a promising treatment for Glycogen Storage Disease Type Ia because it uses adeno-associated virus (AAV) vectors, which are effective in delivering genes to cells. AAV vectors have been shown to successfully increase the activity of important enzymes in cells, which suggests they can help treat genetic diseases like Glycogen Storage Disease Type Ia. ^{3 10 11 12 13}

What makes the treatment DTX401 unique for Glycogen Storage Disease Type Ia?

DTX401 is a gene therapy that uses an adeno-associated virus (AAV) vector to deliver a healthy copy of the gene responsible for Glycogen Storage Disease Type Ia, potentially offering a long-term solution by addressing the root cause of the disease, unlike traditional treatments that only manage symptoms. ^{3 10 11 12 13}

Research Team

Medical Director

Principal Investigator

Ultragenyx Pharmaceutical Inc

Eligibility Criteria

This trial is for individuals with Glycogen Storage Disease Type Ia (GSDIa) who are on a stable regimen of cornstarch therapy. They must be willing to use effective contraception and not plan pregnancy. Excluded are those with liver disease, previous gene therapies, detectable AAV8 antibodies, or certain lab abnormalities.

Inclusion Criteria

I am on a stable cornstarch-based treatment plan for my condition.

I agree to use effective birth control during and after the study for the specified times.

My GSDIa diagnosis was confirmed by genetic testing or liver biopsy.

Exclusion Criteria

I have a liver tumor between 3 and 5 cm that's growing quickly.

You have antibodies to the AAV8 virus before starting the study.

I have had a liver transplant or received liver cell therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single peripheral IV infusion of DTX401 or placebo and are followed closely for 48 weeks

48 weeks

Crossover Treatment

Participants who received placebo are crossed over to receive DTX401, and vice versa, followed closely for an additional 96 weeks

96 weeks

Disease Monitoring Program (DMP)

Participants are followed for at least 10 years post DTX401 infusion

10 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• DTX401
• Oral corticosteroids
• Placebo
• Placebo for oral corticosteroids

Trial Overview The study tests DTX401's ability to reduce reliance on glucose replacement in GSDIa patients versus placebo. It aims to improve glucose control quality over a period of 144 weeks, comparing the effects of an oral corticosteroid treatment against a placebo.

Participant Groups

Group I: DTX401, Then Placebo Experimental Treatment 4 Interventions

Participants receive single peripheral intravenous (IV) infusion of DTX401 in solution. At week 48 participants receive single peripheral IV infusion of Placebo.

Group II: DTX401 (Japan Only) Experimental Treatment 2 Interventions

Participants receive single peripheral intravenous (IV)infusion of DTX401 in solution.

Group III: Placebo, Then DTX401 Placebo Group 4 Interventions

Participants receive single peripheral IV infusion of Placebo. At week 48 eligible participants receive single peripheral IV infusion of DTX401 solution.

Who Is Running the Clinical Trial?

Ultragenyx Pharmaceutical Inc

Lead Sponsor

Trials

94

Recruited

104,000+

Dr. Emil D. Kakkis

Ultragenyx Pharmaceutical Inc

Chief Executive Officer since 2010

MD/PhD in Biological Chemistry from UCLA

Dr. Eric Crombez

Ultragenyx Pharmaceutical Inc

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Findings from Research

A gene therapy using recombinant adeno-associated virus (rAAV) vectors showed promising results in treating a canine model of Glycogen storage disease type Ia (GSDIa), with significant improvements in blood glucose and lactate levels observed after treatment.

The rAAV2/1 vector delivered via the portal vein provided a more sustained correction of glucose homeostasis compared to the initial rAAV2/8 treatment, allowing the dog to thrive without dietary glucose supplementation for 18 months post-treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. Weinstein, DA., Correia, CE., Conlon, T., et al.[2021]

In a study involving three dogs with glycogen storage disease type Ia (GSD Ia), gene therapy using adeno-associated virus (AAV) vectors led to a significant reduction in liver glycogen and improved metabolic parameters, including normalization of fasting glucose and other biochemical markers in one dog two months post-treatment.

The therapy resulted in sustained expression of the glucose-6-phosphatase (G6Pase) enzyme and improved liver histology, indicating the potential of AAV vector gene therapy as a promising treatment for GSD Ia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors. Beaty, RM., Jackson, M., Peterson, D., et al.[2013]

The recombinant adeno-associated virus (AAV) vectors successfully delivered the human glucocerebrosidase (GC) and arylsulfatase A (ASA) genes into murine and patient fibroblasts, leading to significantly increased enzyme activity—15-fold for GC in Gaucher patient cells and up to 500-fold for ASA in metachromatic leukodystrophy cells.

The successful integration of 1-2 copies of the GC and ASA genes into the targeted cell genome demonstrates the potential of these AAV vectors for gene therapy applications in treating related genetic disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of the human glucocerebrosidase and arylsulfatase A genes in murine and patient primary fibroblasts transduced by an adeno-associated virus vector. Wei, JF., Wei, FS., Samulski, RJ., et al.[2012]

AAV2/8 vector-mediated gene therapy significantly improved survival and corrected liver G6Pase deficiency in GSD-Ia mice and dogs, with a 600-fold reduction in the required vector dose compared to previous methods.

This therapy effectively prevented hypoglycemia during fasting and reduced liver glycogen accumulation to near-normal levels, demonstrating its potential as a safe and effective treatment for GSD-Ia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. Koeberl, DD., Pinto, C., Sun, B., et al.[2017]

Gene therapy using a novel adeno-associated virus (AAV) vector successfully prevented mortality and corrected liver glycogen storage in animal models of glycogen storage disease type Ia (GSD-Ia), demonstrating its potential as a new treatment option.

Despite initial success, the therapy faced challenges with the gradual loss of transgene expression, indicating the need for further development and possibly different AAV vector types to maintain long-term efficacy in treating GSD-Ia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In search of proof-of-concept: gene therapy for glycogen storage disease type Ia. Koeberl, DD.[2021]

AAV2/8.TBG.hARSB gene therapy showed no significant toxicity in mice, indicating a favorable safety profile, with only minor transient effects observed.

The therapy effectively targets the liver for gene transfer, which is crucial for treating mucopolysaccharidosis type VI (MPS VI), and the results support moving forward to a phase I/II clinical trial in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI. Ferla, R., Alliegro, M., Marteau, JB., et al.[2020]

The recombinant adeno-associated virus serotype 8 (AAV2/8) vector showed no significant short- or long-term toxicity in a preclinical study, indicating it is safe for use as an adjunctive therapy for Pompe disease.

The AAV2/8 vector effectively increased enzyme activity and reduced glycogen accumulation in tissues, with better efficacy observed in male subjects compared to females, suggesting potential for improved treatment outcomes when combined with enzyme replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. Wang, G., Young, SP., Bali, D., et al.[2020]

AAVrh.10hARSA, a gene therapy vector for treating metachromatic leukodystrophy, was administered safely at a low dose in nonhuman primates, showing no significant adverse effects.

At a high dose, while localized CNS abnormalities were observed, they did not lead to clinical consequences, indicating a need to understand dose limits for safe administration of AAV vectors in the central nervous system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy. Rosenberg, JB., Chen, A., De, BP., et al.[2022]

In a study of 38 individuals receiving systemic AAV9 gene therapy, those treated with corticosteroids experienced significant immune activation, including thrombotic microangiopathy (TMA) and complement pathway activation, indicating potential safety risks associated with this treatment.

In contrast, participants who received a combination of rituximab, sirolimus, and steroids showed minimal immune activation, suggesting that this immunomodulation regimen may enhance the safety of AAV gene therapy by reducing antibody formation and complement activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies. Salabarria, SM., Corti, M., Coleman, KE., et al.[2023]

Adeno-associated virus (AAV) is a safe and effective vector for gene therapy, as it integrates stably into human chromosome 19 and can efficiently transduce various cell types, including blood and nerve cells.

A new method for producing high titer AAV vectors using packaging cell lines and sulfonated cellulose column chromatography could enhance the development and application of AAV-based gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene transfer using adeno-associated virus (AAV) vectors]. Shimada, T.[2012]

A modified AAV2 vector with a bone-targeting peptide (D8) showed significantly higher affinity for hydroxyapatite (HA) and increased gene delivery to bone compared to the unmodified vector, as demonstrated in both in vitro and in vivo studies.

The modified vector maintained comparable physical properties and transduction efficiencies, while achieving 4.7-fold higher enzyme activity in bone three months post-infusion, suggesting a promising strategy for treating systemic bone diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tailoring the AAV2 capsid vector for bone-targeting. Alméciga-Díaz, CJ., Montaño, AM., Barrera, LA., et al.[2023]

Adeno-associated viral (AAV) vectors are generally safe and effective for gene therapy, but their limited cargo capacity of less than 5 kb restricts their use for diseases requiring larger gene transfers.

To address this limitation, researchers are exploring dual vector strategies, where a larger gene is split between two AAV vectors, and various mechanisms to restore full-length gene expression, highlighting ongoing efforts to enhance AAV's therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can Adeno-Associated Viral Vectors Deliver Effectively Large Genes? Tornabene, P., Trapani, I.[2021]

Recombinant adeno-associated virus (AAV) vectors are effective for gene delivery in muscle research, showing potential to treat inherited muscle diseases in animal models and yielding promising results in early clinical trials.

AAV vectors provide robust and long-lasting gene expression in various animal models, and researchers have developed multiple AAV variants to tailor their use for specific muscle gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant adeno-associated viral vector production and purification. Shin, JH., Yue, Y., Duan, D.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Delivery of glucose-6-phosphatase in a canine model for glycogen storage disease, type Ia, with adeno-associated virus (AAV) vectors. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Expression of the human glucocerebrosidase and arylsulfatase A genes in murine and patient primary fibroblasts transduced by an adeno-associated virus vector. [2012]

4. United States pubmed.ncbi.nlm.nih.gov

AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. [2017]

5. United States pubmed.ncbi.nlm.nih.gov

In search of proof-of-concept: gene therapy for glycogen storage disease type Ia. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Non-clinical Safety and Efficacy of an AAV2/8 Vector Administered Intravenously for Treatment of Mucopolysaccharidosis Type VI. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Assessment of toxicity and biodistribution of recombinant AAV8 vector-mediated immunomodulatory gene therapy in mice with Pompe disease. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Thrombotic microangiopathy following systemic AAV administration is dependent on anti-capsid antibodies. [2023]

10. Japan pubmed.ncbi.nlm.nih.gov

[Gene transfer using adeno-associated virus (AAV) vectors]. [2012]

11. United States pubmed.ncbi.nlm.nih.gov

Tailoring the AAV2 capsid vector for bone-targeting. [2023]

12. United States pubmed.ncbi.nlm.nih.gov

Can Adeno-Associated Viral Vectors Deliver Effectively Large Genes? [2021]

13. United States pubmed.ncbi.nlm.nih.gov

Recombinant adeno-associated viral vector production and purification. [2021]