Gene Therapy for Spastic Paraplegia

Age: < 18

Sex: Male

Trial Phase: Phase 1

Sponsor: The Hospital for Sick Children

Must not be taking: Immune suppressants

Disqualifiers: Bleeding disorder, Active infection, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 9

Duration: Single dose

Trial Summary

What is the purpose of this trial?

This will be a first-in-human Phase I, open-label, single dose clinical study of MELPIDA administered intrathecally (IT) through a lumbar puncture (LP) to a single subject with confirmed pathogenic mutations in the Adaptor Related Protein Complex 4 Subunit Mu 1 (AP4M1) gene. The primary outcome will be the determination of the safety and tolerability of MELPIDA in patients with SPG50, based on development of toxicity. The secondary outcome will be a preliminary exploration of efficacy of the treatment. MELPIDA, is a recombinant serotype 9 adeno-associated virus (AAV) encoding a codon-optimized human AP4M1 transgene and will be administer to the patient via a single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg. The total study duration is 5 years post dosing and the participant will be tested at screening/baseline (-28 to -7 days), return for dosing, and then follow-up visits post-dosing on Days 7 (+/-2), 30 (+/-2), 60 (+/-2), 90 (+/-14), 180 (+/-14), 270 (+/-14), 360 (+/-14), 540 (+/-14), and 720 (+/-14) days, then annually for the last 3 years.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it mentions that any chronic drug treatment that creates unnecessary risks for gene transfer may be a concern. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the treatment MELPIDA, AAV9/AP4M1, hAP4M1opt for spastic paraplegia?

Preclinical studies show that the AAV9/AP4M1 gene therapy can partly fix the problems caused by SPG50 in cell and mouse models, with a good safety record in animals. Early treatment and higher doses worked best, suggesting it could be a promising option for treating SPG50. ^{1 2 3 4 5}

Is the gene therapy AAV9/AP4M1 safe for humans?

Preclinical studies on AAV9/AP4M1 gene therapy for spastic paraplegia 50 showed an acceptable safety profile in rodents and monkeys, with minimal-to-mild toxicity observed in some cases. This suggests it may be safe for humans, but further clinical trials are needed to confirm this. ^{1 2 3 6 7}

How is the treatment MELPIDA different from other treatments for spastic paraplegia?

MELPIDA is a gene therapy that uses a virus to deliver a healthy version of the AP4M1 gene directly into the body, aiming to address the root cause of spastic paraplegia 50, unlike current treatments that only manage symptoms. This approach is unique because it targets the genetic defect itself, offering a potential long-term solution rather than just temporary relief. ^{1 3 8 9 10}

Eligibility Criteria

This trial is for children under 5 with SPG50, a genetic disorder affecting movement. They must have specific mutations in the AP4M1 gene and be able to follow study procedures. Kids can't join if they've had other recent treatments, are on certain drugs, or have conditions that make the study's procedures risky.

Inclusion Criteria

Parent/legal guardian willing to provide written informed consent for their child prior to participation in the study

I have SPG50, confirmed by a DNA test showing specific mutations in the AP4M1 gene.

Subject able to comply with all protocol requirements and procedures

Exclusion Criteria

I cannot undergo certain procedures required in this study.

I haven't taken any experimental drugs in the last 30 days and don't plan to during the study.

I am allergic or cannot take MELPIDA or its components.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Single intrathecal infusion of MELPIDA administered through a lumbar puncture

Single dose

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Multiple visits on Days 7, 30, 60, 90, 180, 270, 360, 540, 720, then annually for 3 years

Treatment Details

Interventions

• MELPIDA

Trial Overview The trial tests MELPIDA, a gene therapy delivered directly into spinal fluid to treat SPG50. It's an initial safety test involving one dose and monitoring over five years with several follow-up visits after dosing.

Participant Groups

Group I: MELPIDA Experimental Treatment 1 Intervention

A single intrathecal infusion of 10 mL at 1E14 vg/mL for a total dose of 1E15 vg (open-label)

MELPIDA is already approved in United States, Canada for the following indications:

Approved in United States as MELPIDA for:

• Spastic Paraplegia Type 50 (SPG50)

Approved in Canada as MELPIDA for:

• Spastic Paraplegia Type 50 (SPG50)

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

Findings from Research

AAV-mediated AP4M1 gene replacement therapy shows promise in preclinical studies for treating spastic paraplegia 50 (SPG50), demonstrating the ability to partially rescue functional defects in cellular and mouse models.

The therapy exhibited acceptable safety profiles in both rodent and monkey models, paving the way for potential clinical trials and representing a significant advancement in the search for effective treatments for SPG50.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paving a way to treat spastic paraplegia 50. Brent, JR., Deng, HX.[2023]

AAVrh10, a specific adeno-associated virus serotype, was found to be the most effective for gene delivery in a chronic spinal cord injury mouse model, showing the highest photon count in bioluminescence imaging and greater expression of the reporter protein Venus.

This serotype demonstrated favorable targeting of key cell types in the spinal cord, including neurons, astrocytes, and oligodendrocytes, suggesting its potential as a safe and effective tool for gene therapy in chronic spinal cord injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury. Hoshino, Y., Nishide, K., Nagoshi, N., et al.[2021]

AAV9/AP4M1 gene therapy shows promise for treating spastic paraplegia 50 (SPG50) in preclinical studies, with effective phenotypic rescue observed in patient-derived fibroblasts and significant therapeutic benefits in Ap4m1-KO mice when treated early and with higher doses.

The therapy demonstrated an acceptable safety profile in toxicology studies across various species, including nonhuman primates, indicating that it is safe for potential use in human clinical trials for SPG50.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. Chen, X., Dong, T., Hu, Y., et al.[2023]

The study successfully constructed both wild-type and mutant SPAST vectors to investigate hereditary spastic paraplegia, using COS7 cells for transfection and analysis.

Results showed that while wild-type spastin localized in the plasma membrane, the mutant spastin maintained the same localization and neither form co-localized with microtubules or mitochondria, suggesting a specific role for spastin that does not involve these cellular structures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction of wild-type and mutant SPAST vectors for the study of molecular mechanism of hereditary spastic paraplegia]. Yan, YP., Pu, JL., Zhang, BR., et al.[2019]

Intrathecal delivery of AAV6 or AAV9 vectors was found to be more effective than intraparenchymal injections for gene therapy targeting motor neurons, achieving broader distribution across the spinal cord in adult mice.

Using the cytomegalovirus (CMV) promoter with AAV6 or AAV9 vectors resulted in the highest levels of motor neuron transduction, indicating that both vector choice and promoter selection are crucial for effective gene therapy in motor neuron diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. Snyder, BR., Gray, SJ., Quach, ET., et al.[2011]

In a trial involving 12 patients with hereditary spastic paraplegia (HSP), treatment with dalfampridine for 2 weeks led to significant improvements in walking ability, as measured by the Spastic Paraplegia Rating Scale and the Multiple Sclerosis Walking Scale.

The study found no serious adverse events, suggesting that dalfampridine is a safe option for improving mobility in patients with HSP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dalfampridine in hereditary spastic paraplegia: a prospective, open study. Béreau, M., Anheim, M., Chanson, JB., et al.[2018]

Current treatments for hereditary spastic paraplegias (HSPs) mainly focus on alleviating symptoms but often fall short, highlighting the need for new therapeutic approaches.

Promising treatment targets for HSPs include oxidative stress and microtubule dynamics, with various clinical measures identified to assess treatment efficacy, such as the Spastic Paraplegia Rating Scale and gait velocity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias. Trummer, B., Haubenberger, D., Blackstone, C.[2020]

In a mouse model of Charcot-Marie-Tooth disease type 4J (CMT4J), gene therapy using an AAV9 vector to deliver a human FIG4 sequence significantly improved survival, with treated mice living for at least 1 year compared to an average of 5 weeks for untreated mice.

The treatment also resulted in largely normal motor performance and minimal signs of neuropathy, indicating that AAV9-mediated delivery of FIG4 is both safe and effective in restoring function in this model of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model. Presa, M., Bailey, RM., Davis, C., et al.[2023]

A study of 107 brain MRI scans from 76 individuals with genetically confirmed AP-4-associated hereditary spastic paraplegia (AP-4-HSP) revealed a distinct imaging signature that includes a thin splenium of the corpus callosum and absent or thin anterior commissure, which can help diagnose the condition with about 99% sensitivity.

The research also found that reduced white matter volume correlates with the severity of motor symptoms, and some patients exhibited polymicrogyria, which is linked to a higher risk of seizures, highlighting the importance of early diagnosis and understanding the role of the AP-4 complex in brain development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia. Ebrahimi-Fakhari, D., Alecu, JE., Ziegler, M., et al.[2022]

The study identifies a specific homozygous nonsense variant in the AP4M1 gene (c.1012C>T p.Arg338*) as a cause of AP4 deficiency syndrome, which includes symptoms like hypotonia, spastic paraplegia, and intellectual disability, based on exome sequencing of three patients from consanguineous families in the Middle East.

This variant appears to have a founder effect, suggesting a common ancestor of Turkish origin, as it has been reported in four patients from three other families worldwide, highlighting the genetic link and potential for targeted genetic counseling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families. Becker, A., Felici, C., Lambert, L., et al.[2023]

References

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

Paving a way to treat spastic paraplegia 50. [2023]

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

The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury. [2021]

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

Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. [2023]

4. China pubmed.ncbi.nlm.nih.gov

[Construction of wild-type and mutant SPAST vectors for the study of molecular mechanism of hereditary spastic paraplegia]. [2019]

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

Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. [2011]

6. Germany pubmed.ncbi.nlm.nih.gov

Dalfampridine in hereditary spastic paraplegia: a prospective, open study. [2018]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias. [2020]

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

AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model. [2023]

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

Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia. [2022]

10. Denmark pubmed.ncbi.nlm.nih.gov

Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families. [2023]