Gene Therapy for Spastic Paraplegia

Overseen By Sydney Cooper, MSc

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Elpida Therapeutics SPC

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: 1

Duration: 1 day

4 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a gene therapy treatment called MELPIDA for individuals with SPG50, a rare condition affecting nerve cells and causing muscle stiffness and movement issues. The main goal is to determine if MELPIDA is safe and tolerable for patients. Researchers will also assess its effectiveness in reducing SPG50 symptoms. The trial seeks participants aged 4 months to 10 years who have been diagnosed with SPG50 and can stand for more than 5 seconds or take 5 steps independently or with assistance. As a Phase 1, Phase 2 trial, this research aims to understand how MELPIDA works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking treatment development.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions that if you have a condition requiring chronic drug treatment that poses risks for gene transfer, you may be excluded. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that MELPIDA is likely to be safe for humans?

Research shows that MELPIDA, a gene therapy for hereditary spastic paraplegia type 50 (SPG50), appears safe. Studies have tested MELPIDA by injecting it directly into the spine to target nerve cells. These studies found that the treatment was well-tolerated at certain doses, meaning patients did not experience severe side effects.

Before human testing, animal research also indicated the treatment's safety. These tests helped determine a dose that is both effective and safe, reducing potential risks to patients.

Although MELPIDA remains in early clinical trials, more advanced testing is underway, suggesting that earlier tests found the treatment safe enough to proceed. This development is encouraging for those considering joining the trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for spastic paraplegia, which often rely on medications to manage symptoms or physical therapy to improve mobility, MELPIDA is a cutting-edge gene therapy. This treatment is unique because it targets the genetic root of the condition rather than just alleviating symptoms. Researchers are excited about MELPIDA because it has the potential to offer a long-term solution by correcting the underlying genetic mutations responsible for spastic paraplegia. This could provide a more effective and lasting impact compared to current therapies.

What evidence suggests that MELPIDA might be an effective treatment for spastic paraplegia?

Research has shown that MELPIDA, a gene therapy under investigation in this trial, appears promising in early studies for treating hereditary spastic paraplegia type 50 (SPG50). These studies found that MELPIDA is safe and might help reduce spasticity, a main symptom of SPG50. MELPIDA delivers a healthy version of the AP4M1 gene directly to nerve cells, potentially preventing nerve cell loss linked to SPG50. Although information from human studies remains limited, early results from these initial studies suggest it could positively affect disease symptoms. ^{1 2 3 4 6}

Who Is on the Research Team?

Susan Iannaccone, MD

Principal Investigator

UT Southwestern Medical Center

Are You a Good Fit for This Trial?

Children aged 1-10 with SPG50, a genetic disorder causing paralysis and intellectual disability. They must be able to take steps independently or with help, stand for over 5 seconds, and have a confirmed AP4M1 gene mutation. Excluded are those on certain medications, unable to undergo MRI or lumbar puncture, recently in other trials, or with conditions that interfere with the study.

Inclusion Criteria

I can stand for more than 5 seconds.

My ankle stiffness is mild or moderate.

My SPG50 disease diagnosis was confirmed through genetic testing showing specific mutations in the AP4M1 gene.

Exclusion Criteria

I have a condition that makes spinal taps unsafe for me.

I am allergic or cannot take MELPIDA due to its ingredients.

Enrollment and participation in another interventional clinical trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of MELPIDA via intrathecal injection to deliver a fully functional human AP4M1 cDNA copy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of spasticity and adverse events

60 months

What Are the Treatments Tested in This Trial?

Interventions

• MELPIDA

Trial Overview The trial tests MELPIDA's safety and tolerability through intrathecal injection aimed at delivering functional human AP4M1 cDNA to neurons affected by SPG50. It will monitor adverse events related to treatment and assess any improvements in disease symptoms.

How Is the Trial Designed?

Group I: Treatment Arm Experimental Treatment 1 Intervention

MELPIDA, a gene therapy product

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?

Elpida Therapeutics SPC

Lead Sponsor

Trials

4

Recruited

60+

University of Texas Southwestern Medical Center

Collaborator

Trials

1,102

Recruited

1,077,000+

Cure SPG50

Collaborator

Trials

1

Recruited

4+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06069687

Study Details | NCT06069687 | Administration of MELPIDA ... 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 ...

2. jci.org jci.org/articles/view/164575

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

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36951961/

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

4. nature.com nature.com/articles/s41591-024-03078-4

AAV gene therapy for hereditary spastic paraplegia type 50 The primary outcome was safety, and secondary efficacy measures were related to spasticity. AAV9-AP4M1 was administered at 1 × 1015 vector ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT06692712

NCT06692712 | Phase 3, Open-label Study to Assess the ... This clinical study is a pivotal open-label phase 3 study designed to assess safety and efficacy of MELPIDA in individuals with SPG50. Official Title.

6. clinicaltrial.be clinicaltrial.be/en/details/459188

Phase 3, Open-label Study to Assess the Efficacy and Safe... This clinical study is a pivotal open-label phase 3 study designed to assess safety and efficacy of MELPIDA in individuals with SPG50. Trial ...