NCT05565443: MR-Guided Focused Ultrasound + GCase for Parkinson's Disease

Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT05565443 |
| Title | MR-Guided Focused Ultrasound With Glucocerebrosidase for Parkinson's Disease |
| Status | Recruiting |
| Phase | Phase 1 (Device Trial) |
| Condition(s) | Parkinson's Disease |
| Intervention | MR-guided focused ultrasound (MRgFUS) + GCase (glucocerebrosidase) enzyme delivery |
| Sponsor | InSightec Ltd. |
| Location | Multiple locations (see ClinicalTrials.gov) |

Study Description

Overview

| Field | Value |
|-------|-------|
| NCT Number | NCT05565443 |
| Title | MR-Guided Focused Ultrasound With Glucocerebrosidase for Parkinson's Disease |
| Status | Recruiting |
| Phase | Phase 1 (Device Trial) |
| Condition(s) | Parkinson's Disease |
| Intervention | MR-guided focused ultrasound (MRgFUS) + GCase (glucocerebrosidase) enzyme delivery |
| Sponsor | InSightec Ltd. |
| Location | Multiple locations (see ClinicalTrials.gov) |

Study Description

This Phase 1 clinical trial evaluates the safety and efficacy of combining MR-guided focused ultrasound (MRgFUS) with glucocerebrosidase (GCase) enzyme delivery for treating Parkinson's disease. The approach leverages focused ultrasound to temporarily open the blood-brain barrier (BBB) and enhance delivery of exogenous GCase enzyme to the brain[@fus2023].

Rationale

Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the [GBA1](/proteins/gba1) gene that is critical for glucosylceramide metabolism. Mutations in [GBA1](/genes/gba1) are among the most significant genetic risk factors for Parkinson's disease, and reduced GCase activity contributes to alpha-synuclein aggregation through lysosomal dysfunction[@gcase2024]:

• GBA1 mutations are found in 5-15% of PD patients
• Reduced GCase activity leads to glucosylceramide accumulation
• Glucosylceramide stabilizes toxic alpha-synuclein oligomers
• Enzyme replacement may restore lysosomal function and reduce pathology

Combined Approach

This trial combines two established technologies:

By combining these approaches, the trial aims to achieve therapeutic levels of GCase in the brain without requiring invasive neurosurgery.

Mechanism of Action

Focused Ultrasound-Mediated BBB Opening

MR-guided focused ultrasound works by:

GCase Delivery

Once the BBB is temporarily opened:

Expected Therapeutic Effects

| Effect | Mechanism |
|--------|-----------|
| Reduced glucosylceramide | GCase enzymatic activity |
| Improved lysosomal function | Restoration of autophagy flux |
| Reduced alpha-synuclein | Enhanced clearance of toxic oligomers |
| Neuroprotection | Prevention of dopaminergic neuron loss |

Eligibility Criteria

Inclusion Requirements

• Age: Typically 40-80 years
• Diagnosis: Clinically confirmed Parkinson's disease
• GBA1 mutation status: May require confirmed GBA1 carrier status (check trial details)
• Disease severity: Mild to moderate PD (Hoehn & Yahr stage 1-3)
• Stable medications: No changes in PD medications for specified period
• Ability to undergo MRI

Exclusion Criteria

• Intracranial implants or metallic devices
• Severe neurological comorbidities
• Active psychiatric disorder
• Contraindications to GCase (enzyme replacement therapy)
• Pregnancy or breastfeeding
• Uncontrolled medical conditions

Outcome Measures

Primary Outcomes

| Measure | Description |
|---------|-------------|
| Safety and Tolerability | Incidence of adverse events, serious adverse events |
| BBB Opening Assessment | MRI confirmation of successful BBB opening |

Secondary Outcomes

| Measure | Description |
|---------|-------------|
| GCase Activity | Change in cerebrospinal fluid (CSF) GCase activity |
| Motor Symptoms | Change in MDS-UPDRS score |
| Alpha-Synuclein | Change in CSF alpha-synuclein levels |
| Glucosylceramide | Change in brain glucosylceramide levels (if measured) |

Clinical Significance

Advantages of This Approach

Challenges

• Optimal dosing and treatment frequency not yet established
• Long-term safety of repeated BBB opening unknown
• Requires specialized equipment and expertise
• Patient selection criteria need refinement

Comparison to Other GCase-Targeting Approaches

| Approach | Company | Stage | Mechanism |
|----------|---------|-------|-----------|
| This trial (MRgFUS + GCase) | InSightec | Phase 1 | FUS + enzyme replacement |
| Ambroxol | various | Phase 2/3 | Pharmacological chaperone |
| GZ161 | Sanofi | Preclinical | Gene therapy |
| AAV-GBA1 | Prev. Therapeutics | Preclinical | Gene therapy |

Cross-Links to NeuroWiki

Related Mechanisms

• [GBA1 and GCase in Parkinson's Disease](/mechanisms/gba-therapy-parkinsons)
• [Lysosomal Dysfunction in PD](/mechanisms/lysosomal-dysfunction)
• [Alpha-Synuclein Aggregation](/mechanisms/alpha-synuclein-pathology)
• [Blood-Brain Barrier in Neurodegeneration](/mechanisms/blood-brain-barrier)

Related Proteins and Genes

• [GBA1 Protein](/proteins/gba1)
• [Alpha-Synuclein](/proteins/alpha-synuclein)

Related Therapies

• [Focused Ultrasound for Parkinson's](/therapeutics/focused-ultrasound-parkinson)
• [GCase-Targeting Therapies](/therapeutics/gba-targeting-therapies)
• [Enzyme Replacement Therapy](/therapeutics/enzyme-replacement-therapy)
• [Ambroxol for Parkinson's](/therapeutics/ambroxol-parkinsons)

Related Diseases

• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Gaucher Disease](/diseases/gaucher-disease)

External Links

• [ClinicalTrials.gov - NCT05565443](https://clinicaltrials.gov/study/NCT05565443)
• [InSightec Ltd.](https://www.insightec.com)
• [PubMed - GCase and Parkinson's](https://pubmed.ncbi.nlm.nih.gov/)
• [Focused Ultrasound Foundation](https://www.fusfoundation.org)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving NCT05565443: MR-Guided Focused Ultrasound + GCase for Parkinson's Disease discovered through SciDEX knowledge graph analysis: