Gene Therapy for Giant Axonal Neuropathy

Not currently recruiting at 1 trial location

Overseen By Christopher J Mendoza

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Must not be taking: Levothyroxine, Vitamin A, Tetracycline, others

Disqualifiers: Pregnancy, Ventilator dependence, Infections, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy for individuals with Giant Axonal Neuropathy (GAN), a condition that impairs nerve function and can lead to difficulties with walking, eating, and breathing. The therapy, called scAAV9/JeT-GAN, uses a modified virus to deliver a gene that helps the body produce Gigaxonin, a protein essential for healthy nerves. Researchers aim to determine if this treatment is safe and if it might improve GAN symptoms. Individuals genetically diagnosed with GAN and willing to remain near the study site for a period after treatment may be eligible to participate. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it excludes those using medications that could change intracranial pressure. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this gene transfer treatment is likely to be safe for humans?

Research has shown that scAAV9/JeT-GAN, a gene therapy for Giant Axonal Neuropathy (GAN), has undergone safety testing. In animal studies with mice and monkeys, researchers found no major safety problems, even at high doses. This suggests the treatment might be safe for humans. However, early human studies reported some unwanted effects.

These studies are in the early stages, so researchers are still learning about human responses to the treatment. This phase primarily focuses on assessing safety. Participants might face some risks, but researchers closely monitor everyone to manage any issues that arise. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for Giant Axonal Neuropathy, which are often limited to symptomatic management and supportive care, scAAV9/JeT-GAN represents a novel approach. This gene therapy delivers a healthy copy of the defective gene directly to the patient’s cells using an engineered virus, targeting the root cause of the disorder. Researchers are excited about this treatment because it has the potential to halt or even reverse the progression of the disease, offering hope for a more effective and long-lasting solution.

What evidence suggests that this gene therapy might be an effective treatment for Giant Axonal Neuropathy?

Research has shown that a new treatment, intrathecal gene therapy known as scAAV9/JeT-GAN, might help individuals with Giant Axonal Neuropathy (GAN). This therapy delivers a gene that aids in producing Gigaxonin, a protein crucial for healthy nerves. Previous studies indicated that this treatment might improve movement, although some side effects were reported. Early results suggest potential benefits, but further research is necessary for confirmation. Overall, the treatment has shown promise for GAN patients. Participants in this trial will receive varying doses of scAAV9/JeT-GAN as part of a dose escalation scheme to evaluate its safety and effectiveness. ^{1 2 3 6 7}

Who Is on the Research Team?

Carsten G Bonnemann, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Are You a Good Fit for This Trial?

This trial is for people aged 3 and older diagnosed with Giant Axonal Neuropathy (GAN). Participants must be able to consent, agree to use contraception if of childbearing potential, undergo nerve biopsies, and live near the NIH for a month post-treatment. Pregnant or breastfeeding individuals, those dependent on ventilators, with significant infections or heart issues, prior gene therapy/stem cell transplants, recent immunosuppressive treatments or vaccinations are excluded.

Inclusion Criteria

I am 3 years or older and have a genetic diagnosis of GAN.

I am willing to have a nerve biopsy now and in 12 months.

I agree to use contraception or have a partner who cannot become pregnant for 6 months after treatment.

Exclusion Criteria

Your lab test results show a significant abnormality, according to the doctor.

My lung function is significantly reduced.

You have had bad reactions to the drugs used for anesthesia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phone and in-person visits

Treatment

Participants receive a single dose of scAAV9/JeT-GAN via intrathecal administration

1 day

1 visit (in-person)

Initial Follow-up

Participants are monitored weekly and monthly for safety and efficacy post-treatment

1 month

Weekly visits (in-person)

Long-term Follow-up

Participants are monitored yearly for safety and effectiveness after treatment

15 years

Yearly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• scAAV9/JeT-GAN

Trial Overview

The trial tests scAAV9/JeT-GAN gene transfer via spinal tap injection into cerebrospinal fluid. It aims to deliver functional Gigaxonin genes using a modified virus carrier to help GAN patients. The study involves extensive screening and follow-up over 15 years with various health tests including MRIs and biopsies.

How Is the Trial Designed?

Group I: 5X Experimental Treatment 1 Intervention

3rd dose increase in escalation scheme

Group II: 3.3X Experimental Treatment 1 Intervention

2nd dose increase in escalation scheme

Group III: 1X Experimental Treatment 1 Intervention

Lowest dose in the escalation scheme

Group IV: 10X Experimental Treatment 1 Intervention

Highest dose in the escalation scheme

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

Taysha Gene Therapies, Inc.

Lead Sponsor

Trials

5

Recruited

60+

Published Research Related to This Trial

In newly developed GAN rat models, there was significant degeneration of rod and cone photoreceptor cells in the retina, which may explain the visual impairments seen in children with Giant Axonal Neuropathy (GAN).

The ongoing Phase I gene therapy clinical trial for GAN does not currently address this photoreceptor degeneration, suggesting that future treatments may need to incorporate strategies targeting retinal cells to improve visual outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extensive rod and cone photoreceptor-cell degeneration in rat models of giant axonal neuropathy: implications for gene therapy of human disease. Armao, D., Bouldin, TW., Bailey, RM., et al.[2022]

A single lumbar intrathecal injection of a lentiviral vector successfully delivered the GJB1 gene to Schwann cells in a mouse model of X-linked Charcot-Marie-Tooth Disease, resulting in stable expression in up to 50% of these cells.

This gene therapy approach significantly improved motor performance and nerve function in treated mice, demonstrating potential for a new treatment strategy for inherited demyelinating peripheral neuropathies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy. Kagiava, A., Sargiannidou, I., Theophilidis, G., et al.[2022]

Induced pluripotent stem cells (iPSCs) derived from three GAN patients successfully modeled the disease, showing key pathological features like protein accumulation and aggregate formation, which are characteristic of giant axonal neuropathy.

Introducing gigaxonin into GAN neurons using gene therapy techniques normalized protein levels and eliminated aggregates without harming neuron survival, indicating that gene replacement therapy could be a safe and effective treatment strategy for GAN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin. Johnson-Kerner, BL., Ahmad, FS., Diaz, AG., et al.[2018]

The study successfully evolved two adeno-associated virus (AAV) capsids, AAV-MaCPNS1 and AAV-MaCPNS2, which effectively delivered gene therapy to both the peripheral nervous system (PNS) in rodents and the central nervous system (CNS) in non-human primates, showcasing their potential for treating neuropathologies.

Using AAV-MaCPNS1, researchers demonstrated the ability to deliver a neuronal sensor and actuator in mice, allowing for real-time monitoring of calcium signals and modulation of pain, highlighting the functional utility of these vectors in gene therapy applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems. Chen, X., Ravindra Kumar, S., Adams, CD., et al.[2023]

In a study involving cynomolgus monkeys, administration of recombinant adeno-associated viruses (rAAVs) led to lesions in the dorsal root ganglia (DRG) without causing any observable neurological symptoms or loss of function, indicating a potential safety concern with these vectors.

The observed DRG lesions were linked to transgene overexpression rather than the vector itself, as the non-expressing Null AAV9 vector did not cause lesions despite similar levels of vector DNA, highlighting the importance of monitoring for toxicity related to gene expression in gene therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of AAV-mediated dorsal root ganglionopathy. Buss, N., Lanigan, L., Zeller, J., et al.[2022]

In a study involving 48 adult Wister rats with a 10 mm sciatic nerve gap, the use of glial cell-line derived neurotrophic factor (GDNF) gene modified Schwann cells significantly improved nerve regeneration compared to normal Schwann cells and a control group.

The GDNF-SCs group showed superior results in nerve conduction velocity, reinnervation density, nerve area, and myelin sheath thickness, indicating that GDNF modified cells enhance the repair process of peripheral nerves more effectively than standard treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[An experiment study on repair of peripheral nerve defects by GDNF gene modified Schwann cells]. Ping, P., Li, QF., Zhang, DS.[2006]

AAV1 is the most effective serotype for transducing rat Schwann cells, while AAV2 and AAV6 are equally effective for human Schwann cells, indicating that different AAV serotypes may be needed for different species.

The study highlights that transduction efficiency in cultured Schwann cells does not predict effectiveness in nerve segments, emphasizing the complexity of translating gene therapy from animal models to human applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene delivery to rat and human Schwann cells and nerve segments: a comparison of AAV 1-9 and lentiviral vectors. Hoyng, SA., De Winter, F., Gnavi, S., et al.[2018]

A gene replacement therapy using a lentiviral vector to deliver the human SH3TC2 gene significantly improved motor performance and nerve conduction velocities in a mouse model of Charcot-Marie-Tooth disease type 4C, indicating its potential efficacy.

The treatment also led to structural improvements in myelin thickness and nodal architecture in the peripheral nerves of the mice, suggesting that this approach could effectively address the underlying causes of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy. Schiza, N., Georgiou, E., Kagiava, A., et al.[2020]

AAV2/8 was identified as the most effective adeno-associated vector for transducing Schwann cells in the peripheral nervous system, showing sustained expression for up to 10 weeks after injection, which is crucial for gene therapy applications.

Transduction with AAV2/8 carrying the ciliary neurotrophic factor (CNTF) significantly enhanced markers of nerve regeneration and myelin protein expression, indicating its potential for treating myelin disorders and promoting nerve repair.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration. Homs, J., Ariza, L., Pagès, G., et al.[2019]

AAV9 gene therapy targeting Schwann cells effectively delivered the GJB1 gene, leading to improved motor performance and nerve function in Gjb1-null mice, which model X-linked Charcot-Marie-Tooth disease (CMT1X).

The treatment resulted in enhanced myelination, reduced inflammation in peripheral nerves, and significant improvements in blood biomarkers, suggesting a promising therapeutic approach for CMT1X.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy. Kagiava, A., Karaiskos, C., Richter, J., et al.[2023]

In a study of three Chinese patients with Giant Axonal Neuropathy (GAN), ultrastructural analysis revealed giant axons filled with closely packed neurofilaments, a common pathological feature of the disorder.

One patient with a classical phenotype exhibited irregular tubular-like structures in addition to the giant axons, highlighting distinct structural changes associated with different phenotypes of GAN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heterogeneity of axonal pathology in Chinese patients with giant axonal neuropathy. Wang, L., Zhao, D., Wang, Z., et al.[2014]

All three pediatric patients diagnosed with Giant Axonal Neuropathy (GAN) had biallelic mutations in the GAN gene, confirming the genetic basis of the disorder.

The study highlights the clinical and radiological variability of GAN, emphasizing the importance of genetic testing for accurate diagnosis and patient counseling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Giant Axonal Neuropathy: Clinical, Radiological, and Genetic Features. Garg, M., Kulkarni, SD., Hegde, AU., et al.[2022]

A phase I clinical trial is testing a gene replacement therapy for giant axonal neuropathy (GAN) using an adeno-associated viral vector (AAV9/JeT-GAN), marking the first use of this method in humans.

In preclinical studies, AAV9/JeT-GAN successfully restored normal protein function and improved nerve structure in mice, suggesting it could provide long-term therapeutic benefits for patients with GAN.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy. Bailey, RM., Armao, D., Nagabhushan Kalburgi, S., et al.[2020]

Intravenous delivery of the AAVhu68 vector carrying a human SMN transgene resulted in widespread transduction of spinal motor neurons in juvenile nonhuman primates and piglets, but also caused severe toxicity, including liver failure in one nonhuman primate and proprioceptive deficits in piglets.

The observed toxicities, such as liver damage and sensory neuron degeneration, appear to be direct consequences of high-dose AAV transduction rather than immune responses, suggesting that high systemic doses of AAV vectors may pose risks that need careful monitoring in both preclinical and clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN. Hinderer, C., Katz, N., Buza, EL., et al.[2019]

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pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/38507752/

Intrathecal Gene Therapy for Giant Axonal Neuropathy

Intrathecal gene transfer with scAAV9/JeT-GAN for giant axonal neuropathy was associated with adverse events and resulted in a possible benefit in motor ...

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mdaconference.org

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This work highlights the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer. We further review efficacy in this study.

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clinicaltrialsarena.com

clinicaltrialsarena.com/news/gene-therapy-for-rare-neuropathy-displays-potential-in-nih-trial/

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A first-in-human clinical trial investigating the gene therapy scAAV9/JeT-GAN has shown safety and clinical benefit for patients with giant axonal neuropathy ( ...

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embargoed.www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(16)33619-X

15. Development of Intrathecal scAAV9 Gene Therapy for ...

The safety and biodistribution of scAAV9/JeT-GAN was investigated in mice and non-human primates that received a single IT overdose of scAAV9/JeT-GAN. No safety ...

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S0960896622004205

O.10 First-in-human intrathecal gene transfer study for ...

This study highlights the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer and demonstrates the ability of IT gene transfer ...