We want to help SPG4 research move faster, because it could one day improve the lives of children with SPG4 and their families. But a therapy that targets a genetic cause is built step by step, and every step needs evidence. Here you will find the general path, where research stands today and the studies published by independent teams.
Information checked on
When the gene behind a disease is known, research can try to correct the cause rather than only the symptoms: bring back a missing protein, switch off a harmful one or repair the consequences inside the cell.
The road from idea to treatment is long. Hypotheses are first tested in cells and laboratory animals, then in rigorous safety studies. Only after regulators approve can clinical trials begin, and patient access depends on their results.
In SPG4 the gene has been known since 1999, and several strategies have shown promising results in the laboratory. None has yet reached studies in people, adults or children.
One open question is timing. In a mouse study, a gene therapy given to newborn mice prevented symptoms from appearing; we do not yet know whether treatment would also help after the condition begins. For a condition that can start in childhood, the answer matters, but so far nothing has been tested in children.
Increase the amount of working spastin, for example by blocking its breakdown.
Reduce mutant spastin, which may be toxic — possibly while delivering a healthy copy of the gene.
Medicines that correct microtubule dynamics and its effects in neurons, without changing the gene.
These seven stages describe, in simplified form, how any therapy travels from the lab to patients. They are not milestones completed by the association. For each one, we show where SPG4 research stands today, according to the public sources we checked.
Status on
Where SPG4 research stands today
Stages no SPG4 therapy has reached yet
Where SPG4 research stands today
What the gene does, what goes wrong when it is altered and why certain neurons are affected.
SPG4 today: Published research, ongoing
The gene was discovered in 1999. Spastin’s functions are well studied, but the exact disease mechanism is still debated.
Choosing how the cause might be corrected: a medicine, a gene therapy or another approach.
SPG4 today: Published research, ongoing
Several strategies have been proposed and analysed in scientific reviews.
Testing in human cells, organoids and laboratory animals to see whether the strategy corrects the defects.
SPG4 today: Published research, ongoing
Published results in patient cells, organoids, flies and mice, including a gene therapy tested in mice.
Stages no SPG4 therapy has reached yet
Rigorous dose, toxicology and efficacy studies that justify a first test in people.
SPG4 today: Not yet reached
We found no public evidence that any SPG4 therapy has reached this stage.
Working with regulators: orphan designation, scientific advice and approval of a clinical trial.
SPG4 today: Not yet reached
There is no EU orphan designation for any form of hereditary spastic paraplegia.
Clinical trials in phases (1–3) that test safety, dose and efficacy in people.
SPG4 today: Not yet reached
No trial of a treatment that changes the course of SPG4 is registered on ClinicalTrials.gov or in the EU CTIS register.
Approval by regulators, then reimbursement decisions and organising treatment in medical centres.
SPG4 today: Not yet reached
There is no approved treatment that changes the course of SPG4.
For SPG50 — a different, recessive, childhood-onset disease — a gene therapy moved through several stages within a few years: preclinical studies, including toxicology in three species, a single-patient phase 1 trial, then phase 1/2 and phase 3 trials that were recruiting when we checked. It is not a treatment for SPG4.
We keep the association’s projects strictly separate from research published by others. A study shown here does not mean a partnership, funding or collaboration with its authors.
The association does not yet fund any project. The first call for proposals and its evaluation criteria will be published here.
Are you a researcher? Tell us what you are working onStudies published or publicly registered by teams with no connection to the association, chosen for their relevance to SPG4. We show them because they illustrate what is possible.
Research team: Havlicek S et al. (2014); Rehbach K et al. (2019); Mohan N et al. (2026)
Neurons and brain organoids grown from cells of people with SPG4 make it possible to study the disease in human cells and to screen compounds quickly.
Research team: Sardina F et al. (2020, 2024); Havlicek S et al. (2014)
If the disease stems, at least partly, from too little working spastin, raising the amount of protein could correct the defects. Studies restored spastin levels by blocking its breakdown, in patient cells and fly models.
Research team: Piermarini E, Guha S, Qiang L, et al. (2026)
A viral vector that silences mutant spastin while delivering instructions for healthy spastin (M1 and M87 isoforms). In newborn mice, the treatment prevented corticospinal degeneration and gait problems.
Research team: Mohan N, Ramakrishnan S, Sun X, et al. (2026)
Inhibiting the enzyme HDAC6 restored microtubule acetylation and reduced axonal degeneration in SPG4 organoids, with improved gait in transgenic mice.
Research team: Orso G et al. (2005); Fassier C et al. (2013); Fan Y et al. (2014)
Very low doses of compounds that modify microtubule dynamics corrected defects in fly models, mouse neurons and patient-derived cells.
Research team: University Hospital Tübingen — NCT03206190
Studies the prodromal and early phase of SPG4 using MRI, blood and spinal fluid analyses and electrophysiology. Data like these are needed to design future treatment trials.
The studies below include people with SPG4, but none tests a treatment that changes the disease. They study the natural course, biomarkers, rehabilitation or cognition — information that future treatment trials will need.
As of , no interventional study of a medicine, gene therapy or other treatment that changes the course of SPG4 was registered on ClinicalTrials.gov or in the EU CTIS register. Nor is there any EU orphan designation for hereditary spastic paraplegia.
| Registry | Study | Type | Registry status | Sponsor | Registry update |
|---|---|---|---|---|---|
| NCT03206190(opens in a new tab) | The preSPG4 study: prodromal and early phase of SPG4 | Interventional, no treatment: diagnostic procedures (MRI, lumbar puncture, blood tests, electrophysiology) | Recruiting | University Hospital Tübingen, Germany | |
| NCT06229626(opens in a new tab) | Intensive training programme for HSP SPG4/SPAST | Interventional: rehabilitation | Recruiting | AP-HP, Paris, France | |
| NCT02859428(opens in a new tab) | Natural history and biomarkers in SPG3A, SPG4 and SPG31 | Observational | Terminated (investigator left NIH); 51 participants | NINDS, United States | |
| NCT03104088(opens in a new tab) | Studying cognition in SPG4 | Observational | Completed | University Hospital Tübingen, Germany | |
| NCT03204773(opens in a new tab) | Non-motor symptoms in HSP (SPG4) | Observational | Completed | University Hospital Tübingen, Germany | |
| NCT06260982(opens in a new tab) | Cognitive disorders in HSP type 4 (FDG-PET) | Observational | Unknown | CHU Nancy, France |
The preSPG4 study: prodromal and early phase of SPG4
Intensive training programme for HSP SPG4/SPAST
Natural history and biomarkers in SPG3A, SPG4 and SPG31
Studying cognition in SPG4
Non-motor symptoms in HSP (SPG4)
Cognitive disorders in HSP type 4 (FDG-PET)
Observational registries covering several forms of HSP, including SPG4 (Boston Children’s Hospital, recruiting, registry update ): NCT04712812 (opens in a new tab), NCT05354622 (opens in a new tab), NCT06553976 (opens in a new tab).
Registries change. Check each study’s page before making a decision and talk to your doctor. The association does not recruit participants for these studies.
Search ClinicalTrials.gov(opens in a new tab)The newest studies and reviews in the bibliography we use, each with a plain-language summary.
Review2026
Piermarini E, Baas PW · Movement Disorders 41(10):2592–2605
The most recent review of SPG4 causes and therapeutic directions.
PMID 42538614
Original study2026
Mohan N, Ramakrishnan S, Sun X, et al. · Cell Reports 45(3):117036
Organoids and mice: HDAC6 inhibition rescues axonal degeneration.
PMID 41739645
Original study2026
Piermarini E, Guha S, Qiang L, et al. · Molecular Therapy 34(3):1729–1742
‘Silence-and-replace’ gene therapy in newborn mice: prevented symptoms. Not tested in humans.
PMID 41311060
Original study2026
Zhang D, Hu Y, Guo J, et al. · Movement Disorders 41(3):625–637
Organoids carrying one rare variant: rapamycin restored autophagy.
PMID 41403389
Review2025
Ramakrishnan S, Mohan N, Dong Z, et al. · Movement Disorders 40(3):420–430
The different roles of the two spastin isoforms.
PMID 39614608
Original study2025
Portero D, Xu Q, Hussain A, et al. · Orphanet Journal of Rare Diseases 20(1):363
Case study of how a family initiated the development of Melpida.
PMID 40665386
We want to get to know teams studying SPG4, spastin biology, cell and animal models, or ways for therapies to reach motor neurons. Before our first call for proposals, you can help us understand which questions are priorities and which resources are missing.
Funding can shorten the road from an open question to an answer, for children with SPG4 and their families. Every verified donation appears in our public reporting and supports SPG4 research.
Hazan J, Fonknechten N, Mavel D, et al. (1999). Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nature Genetics 23(3):296–303.
PMID 10610178Last verified: 6 November 2026
Discovery of the SPAST gene and the spastin protein.
Piermarini E, Baas PW (2026). SPG4 hereditary spastic paraplegia: from etiology to therapy. Movement Disorders 41(10):2592–2605.
PMID 42538614Last verified: 6 November 2026
The most recent review of SPG4 causes and therapeutic directions.
U.S. National Library of Medicine (2026). ClinicalTrials.gov — studies listing SPG4 / SPAST (search of 6 November 2026). ClinicalTrials.gov.
clinicaltrials.govLast verified: 6 November 2026
At the time of the search there was no interventional study of a disease-modifying treatment specific to SPG4.
Piermarini E, Guha S, Qiang L, et al. (2026). Intracerebroventricular SPAST-AAV9 gene therapy prevents manifestation of symptoms in a mouse model of SPG4 hereditary spastic paraplegia. Molecular Therapy 34(3):1729–1742.
PMID 41311060Last verified: 6 November 2026
‘Silence-and-replace’ gene therapy in newborn mice: prevented symptoms. Not tested in humans.
Parodi L, Rydning SL, Tallaksen C, Durr A (2019). Spastic Paraplegia 4. GeneReviews®, University of Washington, Seattle (posted 2003; updated 13 June 2019).
PMID 20301339Last verified: 6 November 2026
The core clinical reference for SPG4: frequency, onset, symptoms, inheritance, diagnosis and symptomatic care.
Havlicek S, Kohl Z, Mishra HK, et al. (2014). Gene dosage-dependent rescue of HSP neurite defects in SPG4 patients' neurons. Human Molecular Genetics 23(10):2527–2541.
PMID 24381312Last verified: 6 November 2026
Patient neurons: raising spastin levels corrects defects.
Sardina F, Carsetti C, Giorgini L, et al. (2024). Cul-4 inhibition rescues spastin levels and reduces defects in hereditary spastic paraplegia models. Brain 147(10):3534–3546.
PMID 38551087Last verified: 6 November 2026
Flies and patient cells: restoring spastin levels reduces defects.
Qiang L, Piermarini E, Muralidharan H, et al. (2019). Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse. Human Molecular Genetics 28(7):1136–1152.
PMID 30520996Last verified: 6 November 2026
Evidence for a toxic effect of mutant spastin.
Fassier C, Tarrade A, Peris L, et al. (2013). Microtubule-targeting drugs rescue axonal swellings in cortical neurons from spastin knockout mice. Disease Models & Mechanisms 6(1):72–83.
PMID 22773755Last verified: 6 November 2026
Mouse neurons: microtubule-targeting drugs correct axonal swellings.
Mohan N, Ramakrishnan S, Sun X, et al. (2026). Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology. Cell Reports 45(3):117036.
PMID 41739645Last verified: 6 November 2026
Organoids and mice: HDAC6 inhibition rescues axonal degeneration.
Solowska JM, Baas PW (2015). Hereditary spastic paraplegia SPG4: what is known and not known about the disease. Brain 138(Pt 9):2471–2484.
PMID 26094131Last verified: 6 November 2026
The M1 and M87 spastin isoforms and hypotheses about disease mechanism.
Mohan N, Qiang L, Morfini G, et al. (2021). Therapeutic strategies for mutant SPAST-based hereditary spastic paraplegia. Brain Sciences 11(8):1081.
PMID 34439700Last verified: 6 November 2026
Review of proposed therapeutic strategies for SPG4.
European Medicines Agency (2026). Orphan designations dataset (checked 6 November 2026). European Medicines Agency.
www.ema.europa.euLast verified: 6 November 2026
At the time of checking there was no EU orphan designation for any form of hereditary spastic paraplegia.
Hedera P (2025). Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview. GeneReviews®, University of Washington, Seattle (updated 5 June 2025).
PMID 20301682Last verified: 6 November 2026
Overview of pure hereditary spastic paraplegia and symptomatic treatment options.
Chen X, Dong T, Hu Y, et al. (2023). Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. Journal of Clinical Investigation 133(10):e164575.
PMID 36951961Last verified: 6 November 2026
Preclinical studies for SPG50 gene therapy.
Dowling JJ, Pirovolakis T, Devakandan K, et al. (2024). AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nature Medicine 30(7):1882–1887.
PMID 38942994Last verified: 6 November 2026
First patient treated (SPG50): well tolerated at 12 months, with preliminary signs of stabilisation — not a cure.
U.S. National Library of Medicine (2026). ClinicalTrials.gov — NCT06069687, NCT05518188, NCT06692712 (AAV9/AP4M1 for SPG50). ClinicalTrials.gov.
clinicaltrials.govLast verified: 6 November 2026
Clinical trials of SPG50 gene therapy (not SPG4).
Rehbach K, Kesavan J, Hauser S, et al. (2019). Multiparametric rapid screening of neuronal process pathology for drug target identification in HSP patient-specific neurons. Scientific Reports 9(1):9615.
PMID 31270336Last verified: 6 November 2026
Drug screening in patient-derived neurons.
Sardina F, Pisciottani A, Ferrara M, et al. (2020). Spastin recovery in hereditary spastic paraplegia by preventing neddylation-dependent degradation. Life Science Alliance 3(12):e202000799.
PMID 33106322Last verified: 6 November 2026
Spastin levels can be restored pharmacologically by blocking its degradation.
Orso G, Martinuzzi A, Rossetto MG, et al. (2005). Disease-related phenotypes in a Drosophila model of hereditary spastic paraplegia are ameliorated by treatment with vinblastine. Journal of Clinical Investigation 115(11):3026–3034.
PMID 16276413Last verified: 6 November 2026
Drosophila model: vinblastine attenuates the phenotype.
Fan Y, Wali G, Sutharsan R, et al. (2014). Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia. Biology Open 3(6):494–502.
PMID 24857849Last verified: 6 November 2026
Patient-derived cells: very low doses of tubulin-binding drugs.