AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Outcome Measures and Biomarkers for Clinical Trials in Hereditary Spastic Paraplegia: A Scoping Review.

Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb spasticity. There is no disease-modifying treatment currently available. Therefore, standardized, validated outcome measures to facilitate clinical trials are urgently needed. We performed a scoping review of outcome measures and biomarkers for HSP to provide recommendations for future studies and identify areas for further research. We searched Embase, Medline, Scopus, Web of Science, and the Central Cochrane database. Seventy studies met the inclusion criteria, and eighty-three outcome measures were identified. The Spastic Paraplegia Rating Scale (SPRS) was the most widely used (27 studies), followed by the modified Ashworth Scale (18 studies) and magnetic resonance imaging (17 studies). Patient-reported outcome measures (PROMs) were infrequently used to assess treatment outcomes (28% of interventional studies). Diffusion tensor imaging, gait analysis and neurofilament light chain levels were the most promising biomarkers in terms of being able to differentiate patients from controls and correlate with clinical disease severity. Overall, we found variability and inconsistencies in use of outcome measures with a paucity of longitudinal data. We highlight the need for (1) a standardized set of core outcome measures, (2) validation of existing biomarkers, and (3) inclusion of PROMs in HSP clinical trials.

Paving a way to treat spastic paraplegia 50.

Spastic paraplegia 50 (SPG50) is a rare neurodegenerative disease caused by loss-of-function mutations in AP4M1. There are no effective treatments for SPG50 or any other type of SPG, and current treatments are limited to symptomatic management. In this issue of the JCI, Chen et al. provide promising data from preclinical studies that evaluated the efficacy and safety profiles of an AAV-mediated AP4M1 gene replacement therapy for SPG50. AAV/AP4M1 gene replacement partly rescued functional defects in SPG50 cellular and mouse models, with acceptable safety profiles in rodents and monkeys. This work represents a substantial advancement in therapeutic development of SPG50 treatments, establishing the criteria for taking AAV9/AP4M1 gene therapy to clinical trials.

Online monitoring of focal spasticity treatment with botulinum toxin in people with chronic stroke or hereditary spastic paraplegia: a feasibility study.

OBJECTIVE: To investigate the feasibility and usability of an online spasticity monitoring tool amongst people with hereditary spastic paraplegia or chronic stroke receiving botulinum toxin treatment, and their healthcare providers. METHODS: Mixed methods cohort study, measuring recruitment success and adherence to the monitoring in 3 rehabilitation institutions. In addition, the System Usability Scale (SUS) and interviews with patients and their healthcare providers were used for quantitative and qualitative analysis, respectively. A deductive directed content analysis was used for qualitative evaluation. RESULTS: Of the 19 persons with hereditary spastic paraplegia and 24 with stroke who enrolled in the study, recruitment success and adherence were higher amongst people with hereditary spastic paraplegia compared with stroke. Usability was found "marginal" by rehabilitation physicians and "good" by patients and physical therapists (SUS scores 69, 76, and 83, respectively). According to all participant groups, online monitoring potentially contributes to spasticity management if it is tailored to the actual needs and capabilities of patients, and if it can easily be integrated into the daily/working routines of all users. CONCLUSION: Online monitoring of spasticity in people with hereditary spastic paraplegia or stroke receiving treatment with botulinum toxin may be feasible, provided that the monitoring tool is tailored to the needs of all users.

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

Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay, and subsequent intellectual disability, secondary microcephaly, and epilepsy. We preformed preclinical studies evaluating an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50 and describe in vitro studies that demonstrate transduction of patient-derived fibroblasts with AAV2/AP4M1, resulting in phenotypic rescue. To evaluate efficacy in vivo, Ap4m1-KO mice were intrathecally (i.t.) injected with 5 × 1011, 2.5 × 1011, or 1.25 × 1011 vector genome (vg) doses of AAV9/AP4M1 at P7-P10 or P90. Age- and dose-dependent effects were observed, with early intervention and higher doses achieving the best therapeutic benefits. In parallel, three toxicology studies in WT mice, rats, and nonhuman primates (NHPs) demonstrated that AAV9/AP4M1 had an acceptable safety profile up to a target human dose of 1 × 1015 vg. Of note, similar degrees of minimal-to-mild dorsal root ganglia (DRG) toxicity were observed in both rats and NHPs, supporting the use of rats to monitor DRG toxicity in future i.t. AAV studies. These preclinical results identify an acceptably safe and efficacious dose of i.t.-administered AAV9/AP4M1, supporting an investigational gene transfer clinical trial to treat SPG50.

Spinal cord stimulation may improve gait and cognition in hereditary spastic paraplegia with mental retardation: a case report.

BACKGROUND: Hereditary spastic paraplegia (HSP) include various sporadic and hereditary neurodegenerative disorders, characterized by progressive spasticity and weakness of lower limbs, possibly associated to additional features. CASE PRESENTATION: We report a male HPS patient in his 40 s, showing mental retardation associated with language impairment, dysarthria, and increased urinary frequency. Three months after treatment with electric chronic high-frequency cervical spinal cord stimulation (HF-SCS), he showed an amelioration of motor symptoms (lower limbs spasticity and gait), dysarthria, cognitive functioning (language and constructive praxic abilities), and urinary symptoms (decreased urinary frequency). Single-photon emission computed tomography (SPECT) showed a postoperative increase of cerebral perfusion in right frontal cortex and temporal cortex bilaterally. CONCLUSION: In our patient, HF-SCS might have induced an activation of ascending neural pathways, resulting in changes in activity in various cortical areas (including sensory-motor cortical areas), which may give rise to a modulation of activity in spared descending motor pathways and in neural networks involved in cognitive functions, including language. Although further studies in patients with HPS are needed to clarify whether HF-SCS can be a suitable treatment option in HSP, our observation suggests that HF-SCS, a minimally invasive neurosurgical procedure, might induce beneficial effects of on various symptoms of such orphan disease.

A Randomized Controlled Trial of the Effect of Repetitive Transcranial Magnetic Stimulation of the Motor Cortex on Lower Extremity Spasticity in Hereditary Spastic Paraplegia.

INTRODUCTION: Hereditary spastic paraplegia refers to a group of conditions characterized by a slow progression of spasticity in lower limbs resulting in gait abnormalities. Current treatment options have proven to be insufficient in terms of symptom alleviation. In this study, we tested the effectiveness of repetitive transcranial magnetic stimulation (rTMS) on lower limb spasticity in patients with hereditary spastic paraplegia. METHODS: Eight patients were randomly assigned to receive either five sessions of active 5 Hz-rTMS ( n = 4) or sham rTMS ( n = 4). The primary outcome was a change in spasticity assessed by the modified Ashworth scale. Secondary outcomes were change in 10 m walking test, Fugl-Meyer assessment of lower extremity motor function, and quality-of-life short-form survey scores. Assessment of the outcomes was done before, upon completion, and 1 month after the intervention. We analyzed the data using repeated-measure analysis of variance. RESULTS: Mean age of the participants was 38.5 (SD = 5.4) years, and 50% were women. Compared with sham rTMS, real rTMS was effective in decreasing modified Ashworth scale (rTMS × time: F [df = 2] = 7.44; P = 0.008). Real rTMS group had lower modified Ashworth scale scores at the end of rTMS sessions (estimate = -0.938; SE = 0.295; P = 0.019) and at the end of follow-up (estimate = -0.688; SE = 0.277; P = 0.048) compared with the sham rTMS group. Real and sham rTMS groups were not different in the secondary outcomes. CONCLUSIONS: Repetitive transcranial magnetic stimulation is an effective method in reducing lower limb spasticity of patients with hereditary spastic paraplegia.

The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment.

Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, endoplasmic reticulum shaping, axon transport, endosome trafficking, and mitochondrial function. With the inheritance patterns of autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial inheritance, HSP is prevalent around the globe at a rate of 1-5 cases in every 100,000 individuals. Recent technology and medical interventions somewhat aid in recognizing and managing the malaise. However, HSP still lacks an appropriate and adequate therapeutic approach. Current therapies are based on the clinical manifestations observed in the patients, for example, smoothing the relaxant spastic muscle and physiotherapies. The limited clinical trial studies contribute to the absence of specific pharmaceuticals for HSPs. Our current work briefly explains the causative genes, epidemiology, underlying mechanism, and the management approach undertaken to date. We have also mentioned the latest approved drugs to summarise the available knowledge on therapeutic strategies for HSP.

Modulating brain function with microbiota.

Microbial metabolites identified in animal models and human neurological diseases could be therapeutic targets.

AAV-Mediated Gene Therapy for Glycosphingolipid Biosynthesis Deficiencies.

De novo glycosphingolipid (GSL) biosynthesis defects cause severe neurological diseases, including hereditary sensory and autonomic neuropathy type 1A (HSAN1A), GM3 synthase deficiency, and hereditary spastic paraplegia type 26 (HSPG26), each lacking effective treatment. Recombinant adeno-associated virus (AAV)-mediated gene therapy has emerged as a powerful treatment for monogenic diseases and might be particularly suitable for these neurological conditions.

Improving gait adaptability in patients with hereditary spastic paraplegia (Move-HSP): study protocol for a randomized controlled trial.

BACKGROUND: People with hereditary spastic paraplegia (HSP) experience difficulties adapting their gait to meet environmental demands, a skill required for safe and independent ambulation. Gait adaptability training is possible on the C-Mill, a treadmill equipped with augmented reality, enabling visual projections to serve as stepping targets or obstacles. It is unknown whether gait adaptability can be trained in people with HSP. AIM: The aim of Move-HSP is to study the effects of ten 1-h sessions of C-Mill training, compared with usual care, on gait adaptability in people with pure HSP. In addition, this study aims to identify key determinants of C-Mill training efficacy in people with pure HSP. METHOD: Move-HSP is a 5-week, two-armed, open-label randomized controlled trial with a cross-over design for the control group. Thirty-six participants with pure HSP will be included. After signing informed consent, participants are randomized (1:1) to intervention or control group. All participants register (near) falls for 15 weeks, followed by the first assessment (week 16), and, thereafter, wear an Activ8 activity monitor for 7 days (week 16). The intervention group receives 10 sessions of C-Mill training (twice per week, 1-h sessions; weeks 17-21), whereas control group continues with usual care (weeks 17-21). Afterwards, both groups are re-assessed (week 22). Subsequently, the intervention group enter follow-up, whereas control group receives 10 sessions of C-Mill training (weeks 23-27), is re-assessed (week 28), and enters follow-up. During follow-up, both groups wear Activ8 activity monitors for 7 days (intervention group: week 23, control group: week 29) and register (near) falls for 15 weeks (intervention group: weeks 23-37, control group: weeks 29-43), before the final assessment (intervention group: week 38, control group: week 44). The primary outcome is the obstacle subtask of the Emory Functional Ambulation Profile. Secondary outcomes consist of clinical tests assessing balance and walking capacity, physical activity, and fall monitoring. DISCUSSION: Move-HSP will be the first RCT to assess the effects of C-Mill gait adaptability training in people with pure HSP. It will provide proof of concept for the efficacy of gait adaptability training in people with pure HSP. TRIAL REGISTRATION: Clinicaltrials.gov NCT04180098 . Registered on November 27, 2019.

Spinal direct current stimulation (tsDCS) in hereditary spastic paraplegias (HSP): A sham-controlled crossover study.

Objective: Hereditary spastic paraplegia (HSP) represents a heterogeneous group of neurodegenerative diseases characterized by progressive spasticity and lower limb weakness. We assessed the effects of transcutaneous spinal direct current stimulation (tsDCS) in HSP.Design: A double-blind, randomized, crossover and sham-controlled study.Setting: Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan.Participants: eleven patients with HSP (six men, mean age ± SD: 37.3 ± 8.1 years), eight affected by spastin/SPG4,1 by atlastin1/SPG3a, 1 by paraplegin/SPG7 and 1 by ZFYVE26/SPG15.Interventions: tsDCS (anodal or sham, 2.0 mA, 20', five days) delivered over the thoracic spinal cord (T10-T12).Outcome measures: Motor-evoked potentials (MEPs), the H-reflex (Hr), F-waves, the Ashworth scale for clinical spasticity, the Five Minutes Walking test and the Spastic Paraplegia Rating Scale (SPRS) were assessed. Patients were evaluated before tsDCS (T0), at the end of the stimulation (T1), after one week (T2), one month (T3) and two months (T4).Results: The score of the Ashworth scale improved in the anodal compared with sham group, up to two months following the end of stimulation (T1, P = .0137; T4, P = .0244), whereas the Five Minutes Walking test and SPRS did not differ between the two groups. Among neurophysiological measures, both anodal and sham tsDCS left Hr, F-waves and MEPs unchanged over time.Conclusions: Anodal tsDCS significantly decreases spasticity and might be a complementary strategy for the treatment of spasticity in HSP.

Improved Function in a Runner With Hereditary Spastic Paraparesis With Use of Extracorporeal Shockwave Therapy: Personal Clinical Experience.

ABSTRACT: A 59-yr-old male marathon runner presented with recent diagnosis of hereditary spastic paraplegia in the setting of gait deviation and spasticity. He noted asymmetric wear pattern of his right shoe and toe drag, with recent development of left lower limb pain and cramping attributed to spasticity. He elected to proceed with radial extracorporeal shockwave treatment targeting the affected muscles. The night following initial treatment, he was able to run 2 mins per mile faster over a 4-mile run with resolution of toe drag. He completed six sessions of radial extracorporeal shockwave treatment along with maintaining regular cardiovascular exercise and strength training. He was seen 6 wks after a series of treatment with recent worsening and toe drag that recurred. He completed further sessions with return to improved function seen after his initial series of shockwave and ability to return to running up to 13 miles. His neurologic symptoms remained controlled without noted progression. This case illustrates the potential use of radial extracorporeal shockwave treatment in spasticity management of hereditary spastic paraplegia and that more frequent sessions may be required to maintain benefits of treatment.

Health service experiences among adults with hereditary spastic paraparesis or neurofibromatosis type 1.

BACKGROUND: Persons with rare disorders may experience poorer health services due to limited knowledge about rare disorders among health professionals. Knowledge about how persons with rare disorders perceive health services can help inform service providers to enhance their practices. METHODS: We conducted a self-report survey among adults with the rare disorders hereditary spastic paraparesis (HSP; n = 108; mean age 57.7 years; 54.2% females) and neurofibromatosis type 1 (NF1, n = 142; mean age = 50.3 years; 62.0% females). Their responses concerning perceived health experiences were compared to healthy controls from the population study HUNT-3 (n = 7,312). RESULTS: Both rare disorder groups reported lower satisfaction, trust, and participation in meetings with their general practitioner and specialist health services. More reported health problems were overall associated with poorer health service experiences. CONCLUSION: There is a need to identify predictors of health service experiences at the patient and health service provider levels with the aim to tighten the gap between the health experiences of patients with and without rare disorders.

A historical approach to hereditary spastic paraplegia.

Hereditary spastic paraplegia (HSP) is a group of rare neurological disorders, characterised by their extreme heterogeneity in both their clinical manifestations and genetic origins. Although Charles-Prosper Ollivier d'Angers (1796-1845) sketched out a suggestive description in 1827, it was Heinrich Erb (1840-1921) who described the clinical picture, in 1875, for "spastic spinal paralysis". Jean-Martin Charcot (1825-1893) began teaching the disorder as a clinical entity this same year. Adolf von Strümpell (1853-1925) recognised its hereditary nature in 1880 and Maurice Lorrain (1867-1956) gained posthumous fame for adding his name to that of Strümpell and forming the eponym after his 1898 thesis, the first review covering twenty-nine affected families. He benefited from the knowledge accumulated over a dozen years on this pathology by his teacher, Fulgence Raymond (1844-1910). Here I present a history across two centuries, leading to the clinical, anatomopathological, and genetic description of hereditary spastic paraplegia which today enables a better understanding of the causative cellular dysfunctions and makes it possible to envisage effective treatment.

Non-motor symptoms are relevant and possibly treatable in hereditary spastic paraplegia type 4 (SPG4).

Hereditary spastic paraplegias (HSP) share as cardinal feature progressive spastic gait disorder. SPG4 accounts for about 25% of cases and is caused by mutations in the SPAST gene. Although HSP is an upper motor neuron disease, the relevance of non-motor symptoms is increasingly recognized because of the potential response to treatment. Our study sets out to evaluate non-motor symptoms and their relevance with regard to health-related quality of life. In 118 genetically confirmed SPG4 cases and age- and gender-matched controls, validated questionnaires were used to evaluate fatigue, depression, pain, and restless legs syndrome. In addition, self-reported medical information was collected concerning comorbidities and bladder, bowel, and sexual dysfunction. In a sub-study, cognition was evaluated using the CANTAB® test-battery and the Montreal Cognitive Assessment in 26 SPG4 patients. We found depression and pain to be significantly increased. The frequency of restless legs syndrome varied largely depending on defining criteria. There were no significant deficits in cognition as examined by CANTAB® despite a significant increase in self-reported memory impairment in SPG4 patients. Bladder, sexual, and defecation problems were frequent and seemed to be underrecognized in current treatment strategies. All identified non-motor symptoms correlated with health-related quality of life, which was reduced in SPG4 compared to controls. We recommend that clinicians regularly screen for depression, pain, and fatigue and ask for bladder, sexual, and defecation problems to recognize and treat non-motor symptoms accordingly to improve quality of life in patients with SPG4.

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches.

Hereditary spastic paraplegia (HSP) describes a heterogeneous group of genetic neurodegenerative diseases characterised by progressive spasticity of the lower limbs. The pathogenic mechanism, associated clinical features, and imaging abnormalities vary substantially according to the affected gene and differentiating HSP from other genetic diseases associated with spasticity can be challenging. Next generation sequencing-based gene panels are now widely available but have limitations and a molecular diagnosis is not made in most suspected cases. Symptomatic management continues to evolve but with a greater understanding of the pathophysiological basis of individual HSP subtypes there are emerging opportunities to provide targeted molecular therapies and personalised medicine.

The Effect of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Hereditary Spastic Paraplegia.

Background: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited disorders affecting predominantly the motor cortex and pyramidal tract, which results in slowly progressing gait disorders, as well as spasticity and weakness of lower extremities. Repetitive transcranial magnetic stimulation (rTMS) has been previously investigated as a therapeutic tool for similar motor deficits in a number of neurologic conditions. The aim of this randomized, controlled trial was to investigate the therapeutic potential of rTMS in various forms of HSP, including pure and complicated forms, as well as adrenomyeloneuropathy. Methods: We recruited 15 patients (five women and 10 men; mean age 43.7 ± 10.6 years) with the mentioned forms of HSP. The intervention included five sessions of bilateral 10 Hz rTMS over primary motor areas of the muscles of lower extremities and five sessions of similar sham stimulation. Results: One patient dropped out due to seizure, and 14 patients completed the study protocol. After real stimulation, the strength of the proximal and distal muscles of lower extremities increased, and the spasticity of the proximal muscles decreased. Change in spasticity was still present during follow-up assessment. No effect was observed regarding gait velocity. No changes were seen after sham stimulation. A post hoc analysis revealed an inverse relation between motor threshold and the change of the strength after active rTMS. Conclusions: rTMS may have potential in improving weakness and spasticity of lower extremities in HSP, especially of proximal muscles whose motor areas are located more superficially. This trial is registered with Clinicaltrials.gov NCT03627416.

Functional effects of botulinum toxin type A in the hip adductors and subsequent stretching in patients with hereditary spastic paraplegia.

OBJECTIVE: To investigate the functional effects of bilateral botulinum toxin A treatment and subsequent stretching of spastic hip adductors on gait and reactive lateral stepping responses in patients with pure hereditary spastic paraplegia. DESIGN: Explorative pre-post intervention study. PATIENTS: Twenty-five patients with pure hereditary spastic paraplegia. METHODS: Patients were treated with bilateral botulinum toxin A injections in the hip adductors and performed daily self-administered stretching exercises for 16 weeks. Before the intervention (T0), and 6 (T1) and 16 (T2) weeks thereafter, gait width, gait speed, and leg angles at first stepping-foot contact after lateral balance perturbations were assessed, as well as the corresponding success rates of reactive lateral steps. RESULTS: Compared with baseline, gait width increased by 12.6% and 9.7% and comfortable gait speed by 8.3% and 11.5% at T1 and T2, respectively. In known perturbation directions, leg angles increased by 5.9% at T1 and 8.0% at T2, while success rates increased from 70% at baseline to 90% at T1 and T2. No effects were found for maximal gait speed or lateral stepping responses in unknown perturbation directions. CONCLUSION: Bilateral botulinum toxin A treatment and subsequent stretching of the hip adductors may improve gait and reactive lateral stepping in patients with pure hereditary spastic paraplegia.