Gene Therapy for Giant Axonal Neuropathy

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

21 Participants Needed

Trial Summary

What is the purpose of this trial?

Title: Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy Background: - The Gigaxonin gene lets the body make a protein chemical called Gigaxonin. Nerves need Gigaxonin to work properly. Giant Axonal Neuropathy (GAN) causes a shortage of functional Gigaxonin. Nerves stop working normally in people with GAN. This causes problems with walking and sometimes with eating, breathing, and many other activities. GAN has no cure. Over time, GAN can shorten a person s life. Researchers want to see if a gene transfer treatment may help people with GAN. Objectives: - To see if a gene transfer is safe and shows potential to help people with GAN. Eligibility: - People age 3 and older with GAN. Design: * For 1 month following gene transfer participants must live full-time within 100 miles of the NIH. * Participants will be screened by phone and in person. They will take many tests. Some are listed below. Their medical records will be reviewed. Their caregivers may be contacted. * Participants will have a total of about 27 visits, weekly, monthly, and then yearly over 15 years. They will include many of the tests below. * Physical and nervous system exams. * Blood, urine, and stool samples. * Nerve, lung, heart, and eye tests. * Questionnaires. * MRI scans, nerve biopsies, and spinal taps. Participants will be sedated for some tests. * Speech, memory, muscle, and mobility tests. * Skin biopsy (small sample removed). * Participants will take many medicines. Some require intravenous lines. * Participants will get the gene transfer through an injection by spinal tap into their cerebrospinal fluid, which flows around the brain and spinal cord. The genes are packed in a modified virus that carries the genes to cells in their body. Participants safety is not guaranteed.

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.

What data supports the effectiveness of the treatment scAAV9/JeT-GAN for Giant Axonal Neuropathy?

Research shows that the treatment scAAV9/JeT-GAN restored normal cell structure in lab-grown cells from GAN patients and improved nerve function in mice with the disease. This suggests it could be effective for treating Giant Axonal Neuropathy in humans. ^{1 2 3 4 5}

Is gene therapy using AAV9 generally safe in humans?

Some studies have shown that high doses of AAV9 gene therapy can cause severe side effects, such as liver damage and nerve issues, in animals like monkeys and piglets. However, these effects were observed at high doses, and more research is needed to understand the safety in humans. ^{6 7 8 9 10}

How is the treatment scAAV9/JeT-GAN different from other treatments for Giant Axonal Neuropathy?

The treatment scAAV9/JeT-GAN is unique because it uses gene therapy to target Schwann cells, which are crucial for nerve function, potentially offering a novel approach for conditions like Giant Axonal Neuropathy where no standard treatments exist. This method involves delivering genetic material directly to the nervous system, which is different from traditional drug treatments that do not modify genes. ^{6 11 12 13 14}

Research Team

Carsten G Bonnemann, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England 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. [2022]

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

Heterogeneity of axonal pathology in Chinese patients with giant axonal neuropathy. [2014]

3. India pubmed.ncbi.nlm.nih.gov

Giant Axonal Neuropathy: Clinical, Radiological, and Genetic Features. [2022]

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

Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Intermediate filament protein accumulation in motor neurons derived from giant axonal neuropathy iPSCs rescued by restoration of gigaxonin. [2018]

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

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy. [2022]

7. England pubmed.ncbi.nlm.nih.gov

AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy. [2023]

8. United States 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. [2019]

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

Engineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems. [2023]

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

Characterization of AAV-mediated dorsal root ganglionopathy. [2022]

11. China pubmed.ncbi.nlm.nih.gov

[An experiment study on repair of peripheral nerve defects by GDNF gene modified Schwann cells]. [2006]

12. England pubmed.ncbi.nlm.nih.gov

Schwann cell targeting via intrasciatic injection of AAV8 as gene therapy strategy for peripheral nerve regeneration. [2019]

13. England 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. [2018]

14. England pubmed.ncbi.nlm.nih.gov

Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy. [2020]