Cure SPG52
Research

Research and resources

Where the science stands, who is doing it, and where to go. Verified against ClinicalTrials.gov, PubMed and the organisations' own pages.

Last reviewed 2026-10-21

The registry

Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia, Boston Children's Hospital, ClinicalTrials.gov NCT04712812. Principal investigator Darius Ebrahimi-Fakhari, MD, PhD. A prospective observational registry, estimated 700 participants, running to December 2030, status recruiting [60]. Per Boston Children's, it held nearly 600 patients in October 2025 [9]. Eligibility: symptom onset before 18, currently under 30, genetically confirmed variant in an HSP gene; relatives included. Enrolment is remote and free, with interpreters [37,61].

Study
clinicaltrials.gov/study/NCT04712812
Email
hsp.research@childrens.harvard.edu
Phone
+1 617-355-6388

In Europe, the TreatHSP/SPAX platform in Heidelberg (NCT07798674) is a 30-site natural history study for hereditary spastic paraplegias broadly; AP-4 is not named in its record [62]. Cure AP-4 is building a family-entered data program with RARE-X [37].

The trials

Status as of 2026-10-20, from the ClinicalTrials.gov records and the sponsors' own pages.
ProgramWhere it standsWho can take part
SPG50 (AP4M1), MELPIDA, Phase 3 Enrolling since April 2026 at UT Southwestern (Dallas) and Sant Joan de Déu (Barcelona). About 8 treated children and about 16 untreated concurrent controls; primary endpoint at 156 weeks [31]. The sponsor's stated aim, not a regulatory commitment, is FDA approval by early 2028 [45,46]. Treated: SPG50, ages 4 to 72 months. Controls: SPG47, SPG50 or SPG52, ages 4 to 72 months. Contact studyinfo@elpidatx.com.
SPG50, Phase 1/2 Recruiting in Dallas since February 2023; four children dosed with up to 24 months of follow-up reported in 2024, with a manageable safety profile [30,43]. The first patient, treated in Toronto in 2022, is published [29,41]. About ten children had received SPG50 gene therapy in trials and expanded access by October 2025 [44]. SPG50 only.
SPG47 (AP4B1), BFB-101, Phase 1/2 FDA cleared the application in May 2025 [58]. Registered at Boston Children's for five children aged 12 to 60 months; status "not yet recruiting" [32]. Cure AP-4 states recruitment may begin once funding is secured [37]. SPG47 only, once open.
SPG52 (AP4S1) No SPG52 trial is registered anywhere. The only program is preclinical, at the Universitat Autònoma de Barcelona. See gene therapy for SPG52. Not applicable yet.

The Boston small-molecule program

A screen of 28,864 compounds in patient skin cells, read out by where ATG9A sits, found a lead compound (BCH-HSP-C01) that restores ATG9A trafficking in neurons derived from SPG47 and SPG50 patients [6]. The lead investigator has said it works for all four AP-4 subtypes [9]. As of 2025 to 2026 it reaches the brain in early animal work but clears quickly; work continues on potency, brain exposure and finding its target, with a mouse model and then an FDA application as the stated next steps [9,37]. A 2026 CRISPR screen from the same lab identified two genes whose loss frees ATG9A from the Golgi, one of them flagged as a candidate for therapeutic investigation [38]. A drug-repurposing study commissioned by Cure AP-4 has three existing drugs heading toward an observational study [37]. No human trial of any of these exists.

Organisations

Reading list

Fifteen papers that, together, cover what is known. The full numbered list is at the bottom of the page.

SourceWhy read it
[1] The largest clinical study: 156 patients, 23 with AP4S1. The source of most percentages on this site.
[2] The clinician's reference chapter, updated February 2025, with the evaluation, treatment and surveillance tables.
[20] The MRI study: the four core features and what changes over time.
[17] The only epilepsy cohort that is mostly SPG52: favourable course, no drug resistance.
[3] The paper that first linked AP4S1 to fever-sensitive seizures and showed the complex falls apart without it.
[11] The 2025 SPG52 case series: 43 confirmed cases in the literature, diagnostic pitfalls, and variability within families.
[8] The ATG9A ratio test for uncertain variants.
[21] What matters to caregivers: quality of life tracks motor impairment, and communication ranks first.
[27] Plasma neurofilament light chain as a research biomarker, and the 'severe early' cluster.
[23] Brain changes are visible before birth.
[29] The first SPG50 gene therapy patient, published in Nature Medicine.
[40] The preclinical SPG50 gene therapy work that set the template for the other AP-4 genes.
[57] The preclinical SPG47 gene therapy work from Sheffield.
[6] The Boston small-molecule screen.
[14] The 2011 paper that first described SPG52.

What is not known

No published rate of scoliosis, hip displacement, strabismus, sleep problems or life expectancy in AP-4-HSP. No study of fever management or seizure prevention changing outcomes. No AP-4-specific outcome data for baclofen, botulinum toxin, baclofen pumps or rhizotomy; all treatment evidence is borrowed from general HSP or cerebral palsy practice, or is expert recommendation [2]. No peer-reviewed publication yet of the Barcelona SPG52 preclinical data. No prospective progression paper from the Boston registry. When any of these change, the updates page will say so.

Sources

Numbers in brackets refer to this list. Last reviewed: 2026-10-21. Sources checked on 2026-10-20.

  1. [1] Ebrahimi-Fakhari D, Teinert J, Behne R, et al. Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia. Brain. 2020;143(10):2929-2944. PMID 32979048
  2. [2] Ebrahimi-Fakhari D, Behne R, Davies AK, Hirst J. AP-4-Associated Hereditary Spastic Paraplegia. GeneReviews, University of Washington. Last update February 6, 2025. www.ncbi.nlm.nih.gov/books/NBK535153
  3. [3] Hardies K, May P, Djémié T, et al. Recessive loss-of-function mutations in AP4S1 cause mild fever-sensitive seizures, developmental delay and spastic paraplegia through loss of AP-4 complex assembly. Hum Mol Genet. 2015;24(8):2218-2227. www.ncbi.nlm.nih.gov/pmc/articles/PMC4380070
  4. [6] Saffari A, Brechmann B, Böger C, et al. High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia. Nat Commun. 2024;15:584. PMID 38233389
  5. [8] Agianda HAP, Kim HM, Battaglia N, et al. Diagnostic utility of the ATG9A ratio in AP-4-associated hereditary spastic paraplegia. Ann Clin Transl Neurol. 2026;13(4):834-839. PMID 41491634
  6. [9] Fliesler N. The journey to a treatment for hereditary spastic paraplegia. Boston Children's Answers, October 14, 2025. answers.childrenshospital.org/hereditary-spastic-paraplegia-treatment
  7. [11] Günay Ç, Gazeteci Tekin H. Hereditary spastic paraplegy associated with the AP4S1 gene: a case series highlighting diagnostic pitfalls and phenotypic variability. Mol Syndromol. 2025;16(5):489-497. PMID 41059447
  8. [14] Abou Jamra R, Philippe O, Raas-Rothschild A, et al. Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet. 2011;88(6):788-795. PMID 21620353
  9. [15] Niyoyita S, Uwibambe E, Ndinkabandi J, et al. A rare homozygous AP4S1 variant in Rwandan siblings with autosomal recessive hereditary spastic paraplegia type 52 (SPG52). Genes (Basel). 2025;16(5):542. PMID 40428364
  10. [17] Bartolini E, Ferrari AR, Santorelli FM, et al. Combined generalized and focal epilepsy with reflex features in adaptor protein complex 4-associated hereditary spastic paraplegias: a cohort observational study. Seizure. 2024;121:186-193. PMID 39208719
  11. [18] Carmona S, Marecos C, Amorim M, et al. AP4S1 splice-site mutation in a case of spastic paraplegia type 52 with polymicrogyria. Neurol Genet. 2018;4(5):e273. PMID 30283821
  12. [20] Ebrahimi-Fakhari D, Alecu JE, Ziegler M, et al. Systematic analysis of brain MRI findings in adaptor protein complex 4-associated hereditary spastic paraplegia. Neurology. 2021;97(19):e1942-e1954. PMID 34544818
  13. [21] 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;7(4):e605. PMID 34295967
  14. [23] Brooks AK, Quiroz V, Schierbaum L, et al. Fetal and perinatal brain MRI findings in adaptor protein complex 4-associated hereditary spastic paraplegia. Ann Child Neurol Soc. 2025;3(3):226-231. PMID 41815511
  15. [27] Alecu JE, Saffari A, Ziegler M, et al. Plasma neurofilament light chain is elevated in adaptor protein complex 4-related hereditary spastic paraplegia. Mov Disord. 2023;38(9):1742-1750. www.ncbi.nlm.nih.gov/pmc/articles/PMC10529494
  16. [29] Dowling JJ, Pirovolakis T, Devakandan K, et al. AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med. 2024;30(7):1882-1887. PMID 38942994
  17. [30] ClinicalTrials.gov NCT05518188. A Phase 1/2 open-label intrathecal administration of MELPIDA for SPG50. Sponsor Elpida Therapeutics; collaborator UT Southwestern. Last update posted July 8, 2026. clinicaltrials.gov/study/NCT05518188
  18. [31] ClinicalTrials.gov NCT06692712. Phase 3 open-label study of intrathecal MELPIDA (AAV9/AP4M1) for SPG50 with a matched prospective concurrent control arm. Sponsor Elpida Therapeutics; collaborators UT Southwestern and Hospital Sant Joan de Déu. Start April 1, 2026; last update posted April 20, 2026. clinicaltrials.gov/study/NCT06692712
  19. [32] ClinicalTrials.gov NCT06948019. Safety and efficacy of AAV9/AP4B1 (BFB-101) for patients with SPG47: Phase 1/2 single-center open-label study. Sponsor BlackfinBio; collaborator Boston Children's Hospital. Last update posted April 28, 2025. clinicaltrials.gov/study/NCT06948019
  20. [37] Cure AP-4. Research page (accessed October 20, 2026). cureap4.org/research.php
  21. [38] Ziegler M, Günter C, Alecu JE, et al. CRISPR/Cas9 loss-of-function screen in a neuronal model of AP-4 deficiency identifies ATG9A trafficking modulators. JCI Insight. 2026. PMID 42154535
  22. [40] Chen X, Dong T, Hu Y, et al. Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. J Clin Invest. 2023;133(10):e164575. PMID 36951961
  23. [41] ClinicalTrials.gov NCT06069687. A phase 1 open-label study of intrathecal MELPIDA in patients with SPG50. Sponsor The Hospital for Sick Children. Start March 11, 2022. clinicaltrials.gov/study/NCT06069687
  24. [44] SJD Barcelona Children's Hospital. Gene therapy for SPG50 applied for the first time in Spain. October 22, 2025. www.sjdhospitalbarcelona.org/en/news/first-time-use-gene-therapy-spain-ultra-rare-disease-three-year-old-child-sjd-barcelona-childrens-hospital
  25. [45] LifeArc. Elpida Therapeutics: accelerating gene therapies for ultra-rare neurodegenerative diseases (project page). www.lifearc.org/project/elpida-therapeutics-gene-therapies
  26. [46] LifeArc. LifeArc announces partnership with Elpida Therapeutics to accelerate gene therapies for ultra-rare diseases in children. May 27, 2026. www.lifearc.org/2026/lifearc-partnership-elpida-therapeutics
  27. [56] BlackfinBio. Our pipeline. blackfin.bio/our-pipeline
  28. [57] Wiseman JP, Scarrott JM, Alves-Cruzeiro J, et al. Pre-clinical development of AP4B1 gene replacement therapy for hereditary spastic paraplegia type 47. EMBO Mol Med. 2024;16:2882-2917. www.ncbi.nlm.nih.gov/pmc/articles/PMC11554807
  29. [58] University of Sheffield. FDA approves trial to advance pioneering treatment for hereditary spastic paraplegia (HSP). May 6, 2025. sheffield.ac.uk/news/fda-approves-trial-advance-pioneering-treatment-hereditary-spastic-paraplegia-hsp
  30. [59] National Organization for Rare Disorders (NORD). Spastic paraplegia 52. Last updated August 6, 2024. rarediseases.org/rare-diseases/spastic-paraplegia-52
  31. [60] ClinicalTrials.gov NCT04712812. Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP). Sponsor Boston Children's Hospital; PI Darius Ebrahimi-Fakhari. Last update posted March 18, 2026. clinicaltrials.gov/study/NCT04712812
  32. [61] National Organization for Rare Disorders (NORD). AP-4-associated hereditary spastic paraplegia (AP-4-HSP). Last updated September 26, 2024. rarediseases.org/rare-diseases/ap-4-associated-hereditary-spastic-paraplegia
  33. [62] ClinicalTrials.gov NCT07798674. TreatHSP/SPAX Master Protocol: adaptive natural history platform for ataxias, hereditary spastic paraplegias and spastic ataxias. Sponsor Heidelberg University. Last update posted September 1, 2026. clinicaltrials.gov/study/NCT07798674
  34. [63] Cure AP-4. Home page and Cure SPG52 page. cureap4.org/curespg52.php