SBT101 Gene Therapy for Adrenomyeloneuropathy

(PROPEL Trial)

Recruiting at 1 trial location

Overseen By Clinical Trial Recruitment

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: SwanBio Therapeutics, Inc.

Must not be taking: Steroids, Sirolimus, Tacrolimus, Anesthetics

Disqualifiers: Inflammatory cerebral disease, Diabetes, others

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

Compensation: Varies

Number of Visits: Unknown

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2 randomized, blinded, dose-escalation study to evaluate the safety and efficacy of intrathecal (IT) administration of SBT101, a recombinant adeno-associated virus serotype 9 (AAV9) containing a functional copy of the human adenosine triphosphate (ATP)-binding cassette transporter subfamily D member 1 (ABCD1; hABCD1) gene, in adult patients with adrenomyeloneuropathy (AMN) aged 18-65 years. Patients will receive a single dose of SBT101 via IT route (or an imitation procedure) and will be followed for safety and efficacy for 2 years. Patients receiving SBT101 will be followed for an additional 3 years (5 total) for Safety. Patients receiving an imitation procedure will be offered the opportunity to receive SBT101 after 2 years, as data indicate.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you have contraindications (reasons not to use) for steroids, sirolimus, tacrolimus, or anesthetic medications, you may not be eligible to participate.

What data supports the effectiveness of the SBT101 treatment for Adrenomyeloneuropathy?

Research on a similar gene therapy approach using an adeno-associated viral vector in mice showed a 20% reduction in harmful fatty acids in the spinal cord, which are linked to the disease. This suggests that gene therapy can potentially help manage symptoms of Adrenomyeloneuropathy. ^{1 2 3 4 5}

How does the SBT101 treatment for Adrenomyeloneuropathy differ from other treatments?

SBT101 is a gene therapy that offers a novel approach by potentially targeting the underlying genetic cause of Adrenomyeloneuropathy, unlike traditional treatments that may only address symptoms. This therapy involves delivering a specific gene to affected cells, which could lead to more effective and long-lasting results. ^{6 7 8 9 10}

Eligibility Criteria

Adults aged 18-65 with adrenomyeloneuropathy (AMN), able to walk, diagnosed with X-linked adrenoleukodystrophy (ALD) confirmed by genetic testing and high VLCFA levels. Not eligible if they have unstable adrenal function, prior gene therapy, MRI or anesthesia contraindications, diabetes/high blood sugar, inflammatory brain disease history, or over 15 years since myeloneuropathy onset.

Inclusion Criteria

I have been diagnosed with X-linked adrenoleukodystrophy (ALD) confirmed by genetic testing.

My spinal cord is affected, but I can still walk on my own.

Exclusion Criteria

I have had inflammation in my brain.

I have undergone gene therapy.

I have diabetes or my blood sugar/A1C levels are high.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Escalation

Two doses of SBT101 will be evaluated to establish the maximum tolerated dose

24 months

Regular visits as per study protocol

Dose-Expansion

Additional patients will be enrolled to receive SBT101 at the maximum tolerated dose

24 months

Regular visits as per study protocol

Long-term Safety Follow-up

An unblinded 3-year follow-up period to evaluate the safety of SBT101 and disease progression

3 years

Annual follow-up visits

Treatment Details

Interventions

• Imitation Procedure
• SBT101

Trial Overview The trial is testing SBT101 gene therapy for AMN via a one-time spinal injection compared to an imitation procedure. It's a blind study where patients are monitored for safety and effectiveness over two years; those on SBT101 continue follow-up for three more years.

Participant Groups

Group I: Active Treatment Experimental Treatment 1 Intervention

Patients treated with SBT101

Group II: Imitation Procedure Placebo Group 1 Intervention

Procedure that mimics treatment with SBT101, but does not infuse anything into the spinal cord

Who Is Running the Clinical Trial?

SwanBio Therapeutics, Inc.

Lead Sponsor

Trials

2

Recruited

80+

Findings from Research

Hematopoietic stem cell transplant (HSCT) outcomes for X-linked adrenoleukodystrophy (ALD) have improved significantly due to early detection and better treatment protocols, leading to better management of the disease.

Gene therapy has shown promise in halting disease progression in boys with childhood cerebral ALD, and the implementation of Newborn Screening (NBS) allows for early MRI monitoring, changing the prognosis for this serious neurological condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Landscape of Hematopoietic Stem Cell Transplant and Gene Therapy for X-Linked Adrenoleukodystrophy. Mallack, EJ., Turk, B., Yan, H., et al.[2021]

In a study involving three generations of a family, three adults were diagnosed with adrenomyeloneuropathy and two children with adrenoleukodystrophy, highlighting the importance of recognizing these conditions as different presentations of the same genetic disorder.

The identification of a novel mutation (P543L) in the adrenoleukodystrophy gene, along with elevated levels of very long chain fatty acids, underscores the need for early diagnosis to facilitate genetic counseling and improve future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adrenomyeloneuropathy in patients with 'Addison's disease': genetic case analysis. Mukherjee, S., Newby, E., Harvey, JN.[2022]

The case study highlights adrenomyeloneuropathy, characterized by slowly progressive spastic paraparesis, mild peripheral neuropathy, and adrenal insufficiency.

Dietary therapy has the potential to prevent further progression of neurological symptoms in patients with this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adrenomyeloneuropathy]. Bak, S.[2006]

In a study of 27 Dutch patients with adrenomyeloneuropathy (AMN), 63% developed cerebral demyelination approximately 10.2 years after the onset of symptoms, indicating a higher frequency than previously reported.

The mean survival for these patients was only 3.4 years, suggesting that cerebral demyelination in AMN is associated with a poor prognosis similar to that seen in childhood cerebral adrenoleukodystrophy, highlighting the urgent need for effective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. de Beer, M., Engelen, M., van Geel, BM.[2014]

Using an osmotic pump to deliver adeno-associated viral (AAV) vector into the cerebrospinal fluid of mice allows for efficient gene transfer across the spinal cord, which is crucial for treating adrenoleukodystrophy (ALD).

This method resulted in a 20% reduction in very long-chain fatty acids (VLCFAs) in the spinal cord, while minimizing systemic leakage into organs like the liver and heart, suggesting a safer and more effective approach for gene therapy in neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy. Gong, Y., Berenson, A., Laheji, F., et al.[2020]

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]

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]

An optimized adenoviral vector injection into the sciatic nerve of young rats resulted in peak expression of the lacZ gene between 10 and 14 days with minimal tissue injury, suggesting a safer method for gene therapy in peripheral neuropathy.

In adult mice, the immune response significantly limits the expression of the lacZ gene from adenoviral vectors, but this limitation can be overcome with immunosuppression, indicating potential for using these vectors in gene therapy for conditions like CMT1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of cell-mediated immunity prolongs adenovirus-mediated transgene expression in sciatic nerve. Jani, A., Menichella, D., Jiang, H., et al.[2015]

A herpes simplex virus (HSV)-based vector was developed to regulate erythropoietin (EPO) expression, which can be tightly controlled by doxycycline, showing potential for treating chronic neuropathy.

In a mouse model of diabetes, continuous administration of doxycycline led to significant protection against neuropathy over 3 months, indicating the vector's efficacy and suitability for clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prolonged regulatable expression of EPO from an HSV vector using the LAP2 promoter element. Wu, Z., Mata, M., Fink, DJ.[2021]

Gene therapy using rAAV1.NT-3 delivered to muscle can effectively increase neurotrophin-3 (NT-3) levels in the blood, leading to significant improvements in motor function and nerve health in a mouse model of Charcot-Marie-Tooth disease (CMT1A).

This approach not only establishes a therapeutic dose and a muscle-specific promoter for sustained NT-3 delivery but also sets the stage for future clinical trials in CMT1A and potentially other nerve regeneration disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV1.NT-3 gene therapy for charcot-marie-tooth neuropathy. Sahenk, Z., Galloway, G., Clark, KR., et al.[2022]

References

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

The Landscape of Hematopoietic Stem Cell Transplant and Gene Therapy for X-Linked Adrenoleukodystrophy. [2021]

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

Adrenomyeloneuropathy in patients with 'Addison's disease': genetic case analysis. [2022]

3. Denmark pubmed.ncbi.nlm.nih.gov

[Adrenomyeloneuropathy]. [2006]

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

Frequent occurrence of cerebral demyelination in adrenomyeloneuropathy. [2014]

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

Intrathecal Adeno-Associated Viral Vector-Mediated Gene Delivery for Adrenomyeloneuropathy. [2020]

6. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

Modulation of cell-mediated immunity prolongs adenovirus-mediated transgene expression in sciatic nerve. [2015]

9. England pubmed.ncbi.nlm.nih.gov

Prolonged regulatable expression of EPO from an HSV vector using the LAP2 promoter element. [2021]

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

AAV1.NT-3 gene therapy for charcot-marie-tooth neuropathy. [2022]