Neuronavigation-guided FUS-induced BBB Opening in Alzheimer's Disease Patients and Its Effects on Brain Amyloid and Tau

Summary

The primary purpose of this phase 1b study is to further assess the safety and reversibility of focused ultrasound induced blood-brain barrier opening (FUS-BBBO) in participants with Alzheimer´s Disease (AD) using a single-element transducer with neuronavigation guidance. Preliminary results from our phase 1a study demonstrate that our neuronavigation-guided FUS system was capable of safely and transiently open the BBB in participants with AD. The information collected in this new study may be used to design future clinical trials to ultimately provide a viable alternative for treatment of AD in a safe and noninvasive manner.

Our secondary objective includes the assessment of the therapeutic efficacy of FUS-BBBO in reducing amyloid beta and neurofibrillary tangles, the main hallmark pathologies of AD, using PET tracers. Based on our preclinical studies in AD transgenic mouse models, FUS-BBBO alone was able to reduce both the amyloid beta and tau protein load, resulting in improvements in behavioral tasks assessing memory. Therefore, in this new study, the effect of FUS-BBBO on the amyloid beta and tau protein load in patients with AD will be assessed through the use of PET tracers.

Conditions

• Alzheimer Disease, Early Onset

Interventions

DEVICE

Neuronavigation-guided single-element focused ultrasound transducer

Non-invasive focused ultrasound-induced blood-brain barrier opening will be attempted using a single-element transducer, guided with a neuronavigation system.

DRUG

Lumason

New packages of Lumason microbubbles will be shipped from Bracco Diagnostics Inc. and will be used in conjunction with the ultrasound transducer to temporarily open the BBB. Lumason microbubbles will be freshly activated before treatment sonication and will be drawn using a 10-ml syringe to reach the desired dosage of 0.1mL/kg right before the intravenous injection.

OTHER

Magnetic Resonance Imaging (MRI) with or without gadolinium contrast agents

A high-resolution MRI (with and without gadolinium (Dotarem) contrast agent) will be acquired prior to BBB opening on the GE SIGNATM Premier (3T) (same scanner as in the NHP study) for pre-treatment planning and screening purposes. Then, a second MRI (with and without gadolinium) will be acquired and read by a Board-Certified Radiologist immediately after the treatment sonication in order to assess the BBB opening and safety. Finally, a final follow-up MRI (with and without gadolinium) will be conducted 3 days (±1 day) after the treatment to confirm BBB closing and/or safety. This will be read by a Board-Certified Radiologist as well. All MRI procedures will be performed at the CUIMC/Neurological Institute of New York.

RADIATION

Positron Emission Tomography (PET)

A first PET/CT scan with Amyvid (18F-Florbetapir) and MK-6240 (F18-Florquinitau) tracers will be performed on the SIEMENS Biograph 64 to assess the baseline amyloid plaque load and tau load before the treatment, respectively. Finally, two follow-up PET/CT scans will be conducted 3 weeks (±1 week) and 3 months (±2 weeks) post-treatment to assess amyloid plaque load (using Amyvid) and tau load (using MK-6240).

DRUG

Amyvid

Amyloid PET tracer Amyvid (18F- Florbetapir) will be stored in their original container with proper radiation shielding at 25 °C and only handled by properly trained personnel in the handling and administration of radioactive materials, which requires employing proper radiation protection procedures.

DRUG

MK-6240

\[18F\]MK-6240 will be synthesized, purified, and formulated at the local radiochemistry synthesis laboratory and will be administered as a sterile, pyrogen-free solution by IV injection. The radiotracer \[18F\]MK-6240 is supplied in a sterile, ready-to-use solution, direct from the Columbia University PET Center. It is supplied for a targeted calibration time, the precise volume to be administered at a given time can be calculated based on the decay of F-18. Only personnel properly trained in the handling and administration of radioactive materials should handle \[18F\]MK-6240. Usual radiation protection procedures should be used for handling radiotracers, including shielding (lead or tungsten containers/shields), and personal protective equipment including gloves. There are no specific procedures required for the handling of \[18F\]MK-6240. The expiry of \[18F\]MK-6240 is eight hours from the time at End of Synthesis (EOS).

DRUG

Dotarem

FDA-approved medication. Dotarem will be handled in accordance with the CUMC Research Pharmacy procedures and NYP policy P168, Version 4. Dotarem will be used according to its labeling. 0.2 ml/kg.

DIAGNOSTIC_TEST

Blood draw

Blood samples will be collected through an intravenous catheter or a finger prick during screening, on the day of the FUS treatment and the follow up examinations (week 3 and month 3). These samples will be processed to assess any blood content changes induced by the focused ultrasound treatment.

DEVICE

UR5e

Universal Robots robotic arm used for the accurate positioning of the neuronavigation-guided single-element focused ultrasound transducer with respect to the patient's head.

DIAGNOSTIC_TEST

Urine test

Urine test required following the MRI and PET Centers policy used clinically for pregnancy screening

Sponsors & Collaborators

• Columbia University

  lead OTHER

Principal Investigators

• Grace McIlvain, PhD · Columbia University

Study Design

Allocation

NA

Purpose

DEVICE_FEASIBILITY

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

50 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2027-08-31

Primary Completion

2028-07-31

Completion

2028-12-31

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations