Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)

NCT06948019 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: BCH-CT-SPG47
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

HSP; Hereditary Spastic Paraplegia; Hereditary Spastic Paraparesis; Hereditary Spastic Paraplegia Type 50; Hereditary Spastic Paraplegia Type 47; Hereditary Spastic Paraplegia Type 51; Hereditary Spastic Paraplegia Type 52; SPG47; AP4B1; Neurogenetic Disorders; Neurodevelopmental Conditions; Movement Disorders; Gene Therapy

Keywords

HSP; Hereditary Spastic Paraplegia; Hereditary Spastic Paraplegia Type 50; Hereditary Spastic Paraplegia Type 47; Hereditary Spastic Paraplegia Type 51; Hereditary Spastic Paraplegia Type 52; Hereditary Spastic Paraparesis; Spasticity; Gene Therapy; AAV9; SPG47; AP4B1; AP4M1; AP4E1; AP4S1; movement disorders; neurogenetic conditions; neurodevelopmental conditions

Outcome Measures

Primary Outcomes (1)

• Incidence of unanticipated treatment-related toxicities, Grade 3 or higher in participants with SPG47

  Incidence of unanticipated treatment-related toxicities, Grade 3 or higher, in participants with SPG47 will be determined from the collection of occurrence and severity of serious adverse events (SAEs). Adverse events will be determined according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

  60 months

Secondary Outcomes (2)

• Score of predefined Major Motor Milestones derived from the Gross Motor Function Measure (GMFM-88)

  60 months

• Developmental Milestones

  60 months

Study Arms (1)

Treatment Arm

EXPERIMENTAL

BFB-101, a gene therapy product

Biological: BFB-101 (AAV9-CBh-AP4B1)

Interventions

BFB-101 (AAV9-CBh-AP4B1) BIOLOGICAL

The AAV9-CBh-AP4B1 biological drug product is an aqueous suspension of a gene transfer vector intended for CSF injection. It consists of replication deficient adeno-associated virus (AAV) vector with the AAV serotype 9 capsid enclosing a single stranded DNA with an expression cassette of AP4B1 driven by CBh promoter.

Treatment Arm

Eligibility Criteria

• Age: 12 Months - 60 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and females between the ages of 12 months - 5 years at the time of treatment
• A molecularly confirmed diagnosis of SPG47 (confirmed by a CLIA certified, CE-marked, or equivalent lab): Genomic DNA mutation analysis demonstrating bi-allelic pathogenic variants in the AP4B1 gene.
• Proband must have features of neurologic dysfunction by clinical history and physical examination.
• Stable doses of concomitant medications such as anti-spasticity medications, anti-epileptic medications, behavioral management medications, sleep medications, and special diets, supplements or nutritional support for at least 3 months prior to Screening. If recent changes (\< 3 months) in medications, the participant may be allowed per Investigator judgement.
• Proband must be fully vaccinated per Centers for Disease Control recommendations for childhood vaccinations.
• Two competent custodial parents/guardians with legal capacity (legally acceptable representatives) to execute an Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved consent for medical research must be able to participate in the consent process. If only one parent has sole custody to consent for medical research, then that parent must be able to actively participate in the consent process.
• Legally acceptable representatives must be able to attend all scheduled study visits and provide feedback regarding the participant's symptoms and performance as described in the protocol.
• Legally acceptable representatives agree not to post any of the participant's personal medical data or information related to the study on any website or social media site (e.g., Facebook, Instagram, Twitter, YouTube, etc.) until notified that the study is completed.
• Proband and the proband's family must demonstrate ability to travel to the study center. For the first 30 days post treatment probands will need to stay within a 100-mile radius from the treatment center.

You may not qualify if:

• Inability to participate in the clinical evaluation as determined by the principal investigator.
• Clinically significant abnormal laboratory values (hemoglobin \< 8 or \> 20 g/dL; white blood cell \> 20,000 per cmm, platelets count \< 100,000 per cmm; international normalized ratio \[INR\] \> upper limit of normal \[ULN\]; gamma-glutamyl transferase \[GGT\], alanine aminotransferase \[ALT\], and aspartate aminotransferase \[AST\] or total bilirubin \> 1.5 × ULN, creatinine
• ≥ 1.5 mg/dL) prior to gene replacement therapy.
• Presence of a concomitant medical condition that precludes a cisterna magna or lumbar puncture or use of anesthetics for sedated procedures.
• Bleeding disorder or any other medical condition or circumstance in which a cisterna magna or lumbar puncture is contraindicated according to local institutional policy.
• Documented cardiomyopathy or significant congenital heart abnormalities.
• Inability to be safely sedated in the opinion of the clinical anesthesiologist.
• History of severe/life-threatening allergic reaction to sirolimus, tacrolimus, corticosteroids, or gadolinium.
• Any known history and/or family history of hemophagocytic lymphohistiocytosis (HLH) or multisystem inflammatory syndrome (MIS)
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the investigator creates unnecessary risks for gene transfer.
• Concomitant chronic drug treatment that would cause clinically significant interactions with immunosuppressive agents used in the study.
• Any item which would exclude the participant from being able to undergo magnetic resonance imaging (MRI) according to local institutional policy.
• Any other situation that would exclude the participant from undergoing any other procedure required in this study.
• Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing.
• The presence of significant non-SPG47 related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study.

Sponsors & Collaborators

• BlackfinBio Ltd: lead
• Boston Children's Hospital: collaborator

Study Sites (1)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (6)

• Ebrahimi-Fakhari D, Teinert J, Behne R, Wimmer M, D'Amore A, Eberhardt K, Brechmann B, Ziegler M, Jensen DM, Nagabhyrava P, Geisel G, Carmody E, Shamshad U, Dies KA, Yuskaitis CJ, Salussolia CL, Ebrahimi-Fakhari D, Pearson TS, Saffari A, Ziegler A, Kolker S, Volkmann J, Wiesener A, Bearden DR, Lakhani S, Segal D, Udwadia-Hegde A, Martinuzzi A, Hirst J, Perlman S, Takiyama Y, Xiromerisiou G, Vill K, Walker WO, Shukla A, Dubey Gupta R, Dahl N, Aksoy A, Verhelst H, Delgado MR, Kremlikova Pourova R, Sadek AA, Elkhateeb NM, Blumkin L, Brea-Fernandez AJ, Dacruz-Alvarez D, Smol T, Ghoumid J, Miguel D, Heine C, Schlump JU, Langen H, Baets J, Bulk S, Darvish H, Bakhtiari S, Kruer MC, Lim-Melia E, Aydinli N, Alanay Y, El-Rashidy O, Nampoothiri S, Patel C, Beetz C, Bauer P, Yoon G, Guillot M, Miller SP, Bourinaris T, Houlden H, Robelin L, Anheim M, Alamri AS, Mahmoud AAH, Inaloo S, Habibzadeh P, Faghihi MA, Jansen AC, Brock S, Roubertie A, Darras BT, Agrawal PB, Santorelli FM, Gleeson J, Zaki MS, Sheikh SI, Bennett JT, Sahin M. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020 Oct 1;143(10):2929-2944. doi: 10.1093/brain/awz307.

  PMID: 32979048 BACKGROUND

• Jordan C, Geisel G, Alecu JE, Zhang B, Sahin M, Ebrahimi-Fakhari D. Disease Severity and Motor Impairment Correlate With Health-Related Quality of Life in AP-4-Associated Hereditary Spastic Paraplegia. Neurol Genet. 2021 Jul 20;7(4):e605. doi: 10.1212/NXG.0000000000000605. eCollection 2021 Aug.

  PMID: 34295967 BACKGROUND

• Wiseman JP, Scarrott JM, Alves-Cruzeiro J, Saffari A, Boger C, Karyka E, Dawes E, Davies AK, Marchi PM, Graves E, Fernandes F, Yang ZL, Coldicott I, Hirst J, Webster CP, Highley JR, Hackett N, Angyal A, Silva T, Higginbottom A, Shaw PJ, Ferraiuolo L, Ebrahimi-Fakhari D, Azzouz M. Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47. EMBO Mol Med. 2024 Nov;16(11):2882-2917. doi: 10.1038/s44321-024-00148-5. Epub 2024 Oct 2.

  PMID: 39358605 BACKGROUND

• Alecu J, Schierbaum L, Ebrahimi-Fakhari D. AP-4-Associated Hereditary Spastic Paraplegia. 2018 Dec 13 [updated 2025 Feb 6]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK535153/

  PMID: 30543385 BACKGROUND

• Schierbaum L, Quiroz V, Yang K, Rong J, Battaglia N, Zubair U, Christie M, Davis M, Calame D, Danzi MC, Finkel RS, Burns J, Gilbert DL, Mingbunjerdsuk D, Pruitt G, Pruitt N, Cobb J, Sadjadi R, Cashman CR, Blackstone C, Fink JK, Shy ME, Zuchner S, Ebrahimi-Fakhari D. The Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN): Clinical Trial Readiness for Hereditary Spastic Paraplegia. Neurol Genet. 2025 Feb 21;11(2):e200249. doi: 10.1212/NXG.0000000000200249. eCollection 2025 Apr.

  PMID: 39996129 BACKGROUND

• Agianda HAP, Kim HM, Battaglia N, Rong J, Tam A, Gonzalez Saez-Diez E, Boerkoel CF, Saffari A, Quiroz V, Schierbaum L, Zaman Z, Bernardi K, Ebrahimi-Fakhari D. Diagnostic Utility of the ATG9A Ratio in AP-4-Associated Hereditary Spastic Paraplegia. Ann Clin Transl Neurol. 2026 Jan 5. doi: 10.1002/acn3.70308. Online ahead of print.

  PMID: 41491634 DERIVED

Related Links

• Blackfin Bio

MeSH Terms

Conditions

Spastic Paraplegia, Hereditary; Movement Disorders; Muscle Spasticity

Condition Hierarchy (Ancestors)

Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Central Nervous System Diseases; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Darius Ebrahimi-Fakhari, MD, PhD

CONTACT

617-355-0097; hsp.research@childrens.harvard.edu

Josh Rong, BS

CONTACT

617-355-0903; hsp.research@childrens.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a single-center, Phase 1/2 open-label study to assess the safety and efficacy of a single stereotactic intra-cisterna magna administration of AAV9/AP4B1 in individuals with AP4B1-associated Hereditary Spastic Paraplegia Type 47 (SPG47)

Study Record Dates

• First Submitted: April 22, 2025
• First Posted: April 28, 2025
• Study Start: August 1, 2025
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): August 1, 2032
• Last Updated: April 28, 2025

Record last verified: 2025-04

Locations

US (1)