Advancing Alzheimer's Treatment Through the Blood-Brain Barrier

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Advancing Alzheimer’s Treatment Through the Blood-Brain Barrier

Advancing Alzheimer’s Treatment Through the Blood-Brain Barrier

Breakthrough in Alzheimer’s Disease Treatment: New Method Crosses Blood-Brain Barrier, Published in NEJM.

In recent years, there have been continuous breakthroughs in the treatment of Alzheimer’s Disease (AD).

The U.S. FDA has approved two monoclonal antibodies targeting β-amyloid protein for market release.

Recently, China’s National Medical Products Administration (NMPA) also approved the market application of Eisai’s new drug Lecanemab injection, submitted for the treatment of mild cognitive impairment (MCI) and mild AD dementia related to confirmed β-amyloid pathology.

The mechanism of action of anti-amyloid antibodies involves binding with β-amyloid proteins in the brain to clear their deposits. However, these antibodies face challenges in crossing the blood-brain barrier due to their large molecular size.

Overcoming the blood-brain barrier is a crucial challenge in treating Alzheimer’s and various central nervous system diseases.

A recent study published in the renowned medical journal “The New England Journal of Medicine” (NEJM) reveals a novel approach to reversibly open the blood-brain barrier using low-intensity focused ultrasound, accelerating the clearance of β-amyloid proteins in the brain.

Advancing Alzheimer's Treatment Through the Blood-Brain Barrier

In this study, three patients diagnosed with mild cognitive impairment related to AD received treatment with the anti-amyloid antibody Aducanumab. Although Aducanumab has received accelerated approval from the U.S. FDA for treating Alzheimer’s, its ability to penetrate the blood-brain barrier is limited, requiring prolonged treatment to significantly reduce β-amyloid levels in the brain.

Focused ultrasound, generating mechanical waves, exerts mechanical stress on blood vessel walls, temporarily disrupting the integrity of the blood-brain barrier. This allows therapeutic molecules to diffuse into the brain, with the barrier healing automatically within a few hours. Previous research demonstrated that focused ultrasound aids in delivering antibody drugs to brain metastases.

In this study, while receiving Aducanumab treatment, the three participants underwent focused ultrasound therapy on one hemisphere of the brain. After 6 months of treatment, the researchers measured β-amyloid deposits in the participants’ brains. The results showed a greater reduction in β-amyloid deposits in the brain region treated with focused ultrasound compared to the untreated hemisphere. After 26 weeks of treatment, the average indicator of β-amyloid levels decreased by 32% in the treated brain region compared to the control region.

Cognitive assessments were also conducted on the participants, with two showing no changes in cognitive abilities, behavior, or neuropathology during subsequent follow-ups. The third participant exhibited a decline in cognitive ability scores (RBANS) at the 30-day follow-up, but without changes in neuropathology or daily life ability scores.

Researchers suggest that combining focused ultrasound with Aducanumab in this concept validation clinical trial can safely accelerate the reduction of β-amyloid levels. This aligns with previous preclinical studies showing that ultrasound enhances Aducanumab’s ability to cross the blood-brain barrier.

Apart from focused ultrasound, other techniques are being explored to cross the blood-brain barrier, with the use of transferrin receptor (TfR) progressing rapidly. Roche’s trontinemab, employing the brain shuttle technology, is a targeted anti-amyloid monoclonal antibody that effectively assists antibody penetration through the blood-brain barrier by fusing the monoclonal antibody with a protein domain that can bind to TfR.

Preliminary clinical trial results announced at the end of last year revealed that trontinemab, compared to Roche’s previously developed amyloid-targeting antibody gantenerumab, has an eightfold higher brain cerebrospinal fluid/plasma ratio and more rapidly reduces brain β-amyloid levels.

Denali Therapeutics’ TfR-based delivery system has shown positive results in clinical trials for treating type II mucopolysaccharidosis. The company has also entered a development agreement with Boehringer Ingelheim to enhance the efficacy of anti-amyloid antibodies using this delivery system.

While the blood-brain barrier is a crucial barrier protecting the brain from harmful substances, it also poses a significant obstacle to delivering therapeutic drugs to the brain. This challenge is particularly prominent in treating Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. The hope is that technologies overcoming the blood-brain barrier will receive further validation in clinical trials, paving the way for better treatment options for Alzheimer’s and other central nervous system diseases in the future.

Reference:
[1] The innovation that gets an Alzheimer’s drug through the blood-brain barrier. Retrieved January 15, 2024, from https://www.technologyreview.com/2024/01/12/1086442/the-innovation-that-gets-an-alzheimers-drug-through-the-blood-brain-barrier/
[2] Rezai et al., (2024). Ultrasound Blood–Brain Barrier Opening and Aducanumab in Alzheimer’s Disease. NEJM, DOI: 10.1056/NEJMoa2308719
[3] Hynynen. (2024). Sounding Out the Blood–Brain Barrier. NEJM. DOI: 10.1056/NEJMe2311358