Gene Therapy for Spastic Paraplegia

Overseen By Josh Rong, BS

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: BlackfinBio Ltd

Must be taking: Anti-spasticity, Anti-epileptic

Must not be taking: Immunosuppressive interactions

Disqualifiers: Cardiomyopathy, CNS impairment, others

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

Compensation: Varies

Number of Visits: 7

Duration: 1 day

5 Participants Needed

Trial Summary

What is the purpose of this trial?

Safety and Efficacy of AAV9/AP4B1 For Patients with AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47): A Phase 1/2 Single-Center, Open-Label Study of Stereotactic Intra-cisterna Magna Administration. The goal of this clinical trial is to evaluate whether a gene therapy can safely treat children with SPG47, a rare genetic condition that causes progressive spasticity and developmental delays. The main questions it aims to answer are: * Is the gene therapy safe and well tolerated? * Does the gene therapy improve motor function and developmental outcomes? Participants will: * Undergo screening assessments to confirm eligibility * Receive a single dose of the gene therapy vector * Attend follow-up visits for safety monitoring and developmental assessments over the course of five years

Do I have to stop taking my current medications for the trial?

The trial does not require you to stop taking your current medications, but your doses must be stable for at least 3 months before screening. If there have been recent changes in your medications, the investigator will decide if you can still participate.

What data supports the effectiveness of the treatment BFB-101 (AAV9-CBh-AP4B1) for spastic paraplegia?

Preclinical studies show that a similar gene therapy using AAV9/AP4M1 can partly fix the problems in cells and mice with spastic paraplegia 50, and it was safe in animals. This suggests that the treatment might help people with this condition. ^{1 2 3 4 5}

Is the gene therapy BFB-101 (AAV9-CBh-AP4B1) safe for humans?

Preclinical studies in mice, rats, and nonhuman primates showed that the gene therapy AAV9/AP4M1, similar to BFB-101, had an acceptable safety profile up to a target human dose, with only minimal-to-mild side effects observed. ^{1 2 3 6 7}

What makes the gene therapy BFB-101 unique for treating spastic paraplegia?

BFB-101 is a novel gene therapy that uses an adeno-associated virus (AAV) to deliver a functional copy of the AP4B1 gene directly to the spinal cord, aiming to address the root cause of spastic paraplegia rather than just managing symptoms. This approach is unique because there are currently no effective treatments for spastic paraplegia, and BFB-101 offers a potential disease-modifying option. ^{1 2 3 7 8}

Eligibility Criteria

This trial is for children with a rare genetic disorder called SPG47, which leads to progressive muscle stiffness and developmental delays. Participants must pass screening assessments confirming their condition.

Inclusion Criteria

Proband must be fully vaccinated per CDC recommendations

Legally acceptable representatives must attend all scheduled study visits and provide feedback

Legally acceptable representatives agree not to post participant's data on social media until study completion

Exclusion Criteria

Failure to obtain appropriate informed consent

Clinically significant abnormal laboratory values prior to gene replacement therapy

Inability to be safely sedated according to clinical anesthesiologist

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive a single dose of the gene therapy vector via intra-cisterna magna injection

1 day

1 visit (in-person)

Follow-up

Participants attend follow-up visits for safety monitoring and developmental assessments

60 months

Regular visits over 5 years

Treatment Details

Interventions

• BFB-101 (AAV9-CBh-AP4B1)

Trial Overview The study tests the safety and effectiveness of BFB-101 (AAV9-CBh-AP4B1), a gene therapy administered once into the fluid surrounding the brain and spinal cord, in improving motor function and development over five years.

Participant Groups

Group I: Treatment Arm Experimental Treatment 1 Intervention

BFB-101, a gene therapy product

Who Is Running the Clinical Trial?

BlackfinBio Ltd

Lead Sponsor

Boston Children's Hospital

Collaborator

Trials

801

Recruited

5,584,000+

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]

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. China pubmed.ncbi.nlm.nih.gov

[Transfection of exogenous gene: Lac Z into spinal cord of SD rats and its protein expression:an in vivo study]. [2012]

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

Improved gene delivery to adult mouse spinal cord through the use of engineered hybrid adeno-associated viral serotypes. [2023]

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

AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials. [2019]

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

Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J. [2022]