Gene Therapy for Spastic Paraplegia
Recruiting in Palo Alto (17 mi)
Age: < 18
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Elpida Therapeutics SPC
Must not be taking: Immune suppressants
Disqualifiers: Bleeding disorder, Active infection, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial tests MELPIDA, a gene therapy for patients with SPG50, a severe neurological disorder. MELPIDA aims to deliver a healthy gene to nerve cells to help them function properly and slow down the disease. Gene therapy has shown positive outcomes in treating complex neurological disorders, including amyotrophic lateral sclerosis, Parkinson's disease, and others.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it mentions that if you have a condition requiring chronic drug treatment that poses risks for gene transfer, you may be excluded. It's best to discuss your specific medications with the trial team.
What data supports the effectiveness of the treatment MELPIDA, AAV9/AP4M1, hAP4M1opt for spastic paraplegia?
Preclinical studies show that the AAV9/AP4M1 gene therapy can partly fix the problems in cells and mice with spastic paraplegia 50, and it is safe in animals like rodents and monkeys. This suggests it might help treat this condition in humans.
12345Is the gene therapy AAV9/AP4M1 safe for humans?
Preclinical studies on AAV9/AP4M1 gene therapy for spastic paraplegia 50 showed an acceptable safety profile in animals like mice, rats, and monkeys, with minimal-to-mild side effects observed. This suggests it may be safe for humans, but more research is needed to confirm this.
23467How is the treatment MELPIDA different from other treatments for spastic paraplegia?
MELPIDA is a gene therapy that uses a virus to deliver a healthy version of the AP4M1 gene directly into the spinal fluid, aiming to address the root cause of spastic paraplegia 50, unlike current treatments that only manage symptoms.
248910Eligibility Criteria
Children aged 1-10 with SPG50, a genetic disorder causing paralysis and intellectual disability. They must be able to take steps independently or with help, stand for over 5 seconds, and have a confirmed AP4M1 gene mutation. Excluded are those on certain medications, unable to undergo MRI or lumbar puncture, recently in other trials, or with conditions that interfere with the study.Inclusion Criteria
I can stand for more than 5 seconds.
My ankle stiffness is mild or moderate.
My SPG50 disease diagnosis was confirmed through genetic testing showing specific mutations in the AP4M1 gene.
+5 more
Exclusion Criteria
I have a condition that makes spinal taps unsafe for me.
I am allergic or cannot take MELPIDA due to its ingredients.
Enrollment and participation in another interventional clinical trial
+11 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a single dose of MELPIDA via intrathecal injection to deliver a fully functional human AP4M1 cDNA copy
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, with assessments of spasticity and adverse events
60 months
Participant Groups
The trial tests MELPIDA's safety and tolerability through intrathecal injection aimed at delivering functional human AP4M1 cDNA to neurons affected by SPG50. It will monitor adverse events related to treatment and assess any improvements in disease symptoms.
1Treatment groups
Experimental Treatment
Group I: Treatment ArmExperimental Treatment1 Intervention
MELPIDA, a gene therapy product
MELPIDA is already approved in United States, Canada for the following indications:
🇺🇸 Approved in United States as MELPIDA for:
- Spastic Paraplegia Type 50 (SPG50)
🇨🇦 Approved in Canada as MELPIDA for:
- Spastic Paraplegia Type 50 (SPG50)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Medical Center DallasDallas, TX
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Who Is Running the Clinical Trial?
Elpida Therapeutics SPCLead Sponsor
University of Texas Southwestern Medical CenterCollaborator
Cure SPG50Collaborator
References
[Construction of wild-type and mutant SPAST vectors for the study of molecular mechanism of hereditary spastic paraplegia]. [2019]To construct wild-type and mutant pEGFP SPAST vectors and to explore the molecular mechanism of hereditary spastic paraplegia.
Paving a way to treat spastic paraplegia 50. [2023]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.
The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury. [2021]Treatment options for chronic spinal cord injury (SCI) remain limited due to unfavourable changes in the microenvironment. Gene therapy can overcome these barriers through continuous delivery of therapeutic gene products to the target tissue. In particular, adeno-associated virus (AAV) vectors are potential candidates for use in chronic SCI, considering their safety and stable gene expression in vivo. Given that different AAV serotypes display different cellular tropisms, it is extremely important to select an optimal serotype for establishing a gene transfer system during the chronic phase of SCI. Therefore, we generated multiple AAV serotypes expressing ffLuc-cp156, a fusion protein of firefly luciferase and Venus, a variant of yellow fluorescent protein with fast and efficient maturation, as a reporter, and we performed intraparenchymal injection in a chronic SCI mouse model. Among the various serotypes tested, AAVrh10 displayed the highest photon count on bioluminescence imaging. Immunohistological analysis revealed that AAVrh10 showed favourable tropism for neurons, astrocytes, and oligodendrocytes. Additionally, with AAVrh10, the area expressing Venus was larger in the injury epicentre and extended to the surrounding tissue. Furthermore, the fluorescence intensity was significantly higher with AAVrh10 than with the other vectors. These results indicate that AAVrh10 may be an appropriate serotype for gene delivery to the chronically injured spinal cord. This promising tool may be applied for research and development related to the treatment of chronic SCI.
Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies. [2023]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.
Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. [2011]Gene therapy for motor neuron diseases requires efficient gene delivery to motor neurons (MNs) throughout the spinal cord and brainstem. The present study compared adeno-associated viral (AAV) vector serotypes 1, 6, 8, and 9 for spinal cord delivery in adult mice, by the intraparenchymal or intrathecal route of administration. Whereas intraparenchymal injections resulted in local transduction of the lumbar segment of the spinal cord, intrathecal injections led to a broader distribution, transducing cells along the sacral, lumbar, and lower thoracic spinal cord. Overall, AAV6 and AAV9 performed better than the other serotypes. Dramatic differences in cell-specific expression patterns could be observed when constructs bearing the chicken β-actin (Cba) versus cytomegalovirus (CMV) promoter were compared. In summary, intrathecal delivery of AAV6 or AAV9 vectors containing the CMV promoter yielded the strongest levels of biodistribution and MN transduction in the spinal cord.
Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias. [2020]Hereditary spastic paraplegias (HSPs) are a large group of genetically-diverse neurologic disorders characterized clinically by a common feature of lower extremity spasticity and gait difficulties. Current therapies are predominantly symptomatic, and even then usually provide inadequate relief of symptoms. Going forward, HSP therapeutics development requires a systematic analysis of quantifiable measures and tools to assess treatment response. This review summarizes promising therapeutic targets, assessment measures, and previous clinical trials for the HSPs. Oxidative stress, signaling pathways, microtubule dynamics, and gene rescue/replacement have been proposed as potential treatment targets or modalities. Quantitative evaluation of pre-clinical rodent HSP models emphasize rotarod performance, foot base angle, grip strength, stride length, beam walking, critical speed, and body weight. Clinical measures of HSP in humans include 10-m gait velocity, the Spastic Paraplegia Rating Scale (SPRS), Ashworth Spasticity Scale, Fugl-Meyer Scale, timed up-and-go, and the Gillette Functional Assessment Questionnaire. We conducted a broad search for past clinical trials in HSPs and identified trials that investigated pharmacological agents including atorvastatin, gabapentin, L-threonine, botulinum toxin, dalfampridine, methylphenidate, and baclofen. We provide recommendations for future HSP treatment directions based on these prior research experiences as well as regulatory insight.
Dalfampridine in hereditary spastic paraplegia: a prospective, open study. [2018]Our aim was to support the use of dalfampridine as a treatment for patients affected with hereditary spastic paraplegia (HSP). We performed a prospective, uncontrolled, proof of concept, open trial. We included 12 HSP patients defining the total group (TG) who received dalfampridine 10 mg twice daily for 2 weeks. Efficacy assessment was based on walking ability improvement. The Timed-25-Foot Walk Test, the Spastic Paraplegia Rating Scale (SPRS), and the 12-item Multiple Sclerosis Walking Scale (MSWS-12) were performed before and after treatment. Safety assessment was based on adverse events occurrence. A significant improvement in SPRS (p = 0.0195) and MSWS-12 (p = 0.0429) was noted after treatment in the TG. No serious adverse events were noted. This interventional study provides encouraging results supporting the use of dalfampridine in HSP.
AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model. [2023]Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive, loss-of-function mutations in FIG4, encoding a phosphoinositol(3,5)P2-phosphatase. CMT4J patients have both neuron loss and demyelination in the peripheral nervous system, with vacuolization indicative of endosome/lysosome trafficking defects. Although the disease is highly variable, the onset is often in childhood and FIG4 mutations can dramatically shorten life span. There is currently no treatment for CMT4J. Here, we present the results of preclinical studies testing a gene-therapy approach to restoring FIG4 expression. A mouse model of CMT4J, the Fig4-pale tremor (plt) allele, was dosed with a single-stranded adeno-associated virus serotype 9 (AAV9) to deliver a codon-optimized human FIG4 sequence. Untreated, Fig4plt/plt mice have a median survival of approximately 5 weeks. When treated with the AAV9-FIG4 vector at P1 or P4, mice survived at least 1 year, with largely normal gross motor performance and little sign of neuropathy by neurophysiological or histopathological evaluation. When mice were treated at P7 or P11, life span was still significantly prolonged and peripheral nerve function was improved, but rescue was less complete. No unanticipated adverse effects were observed. Therefore, AAV9-mediated delivery of FIG4 is a well-tolerated and efficacious strategy in a mouse model of CMT4J.
Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia. [2022]AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations.
Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families. [2023]Bi-allelic variants affecting one of the four genes encoding the AP4 subunits are responsible for the "AP4 deficiency syndrome." Core features include hypotonia that progresses to hypertonia and spastic paraplegia, intellectual disability, postnatal microcephaly, epilepsy, and neuroimaging features. Namely, AP4M1 (SPG50) is involved in autosomal recessive spastic paraplegia 50 (MIM#612936). We report on three patients with core features from three unrelated consanguineous families originating from the Middle East. Exome sequencing identified the same homozygous nonsense variant: NM_004722.4(AP4M1):c.1012C>T p.Arg338* (rs146262009). So far, four patients from three other families carrying this homozygous variant have been reported worldwide. We describe their phenotype and compare it to the phenotype of patients with other variants in AP4M1. We construct a shared single-nucleotide polymorphism (SNP) haplotype around AP4M1 in four families and suggest a probable founder effect of Arg338* AP4M1 variant with a common ancestor most likely of Turkish origin.