PureTech hails new avenue for Alzheimer’s disease treatment

By Jane Byrne contact

- Last updated on GMT

© GettyImages/Urupong
© GettyImages/Urupong

Related tags: Alzheimer's disease, antibodies, AAV platform

Preclinical research, published in Nature, suggests a new avenue for Alzheimer’s disease (AD) treatment, through restoring lymphatic flow in the brain

AD is the most prevalent cause of dementia and, currently, there is no effective treatment.

Led by Dr Jonathan Kipnis, professor of pathology and immunology at Washington University School of Medicine, working with PureTech scientists, the study​ suggests that enhancing meningeal lymphatic drainage could improve clinical outcomes in AD, either alone or in combination with passive immunotherapies, such as antibodies directed at amyloid beta (Aβ).

Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, according to the team, and the study indicates that clinical outcomes of AD could be improved by restoring healthy drainage patterns.

The new paper builds on foundational research​ published in Nature​ in 2018, in which Dr Kipnis’s lab showed that disrupting meningeal lymphatic drainage promoted Aβ accumulation in preclinical models of Alzheimer’s disease.

The more recent work finds that improving meningeal lymphatic drainage enhances Aβ clearance in conjunction with passive immunotherapies and modulates microglia activation to improve neural tissue homeostasis in aged transgenic Alzheimer’s disease mice.

PureTech holds an exclusive license to the underlying intellectual property. The company said it is aiming to advance this work via its wholly-owned meningeal lymphatics research program, which is targeting a range of neurodegenerative and neuroinflammatory diseases.

Halting AD progression

We asked Joe Bolen, PhD, chief scientific officer at PureTech, to spell out more clearly the meaning of “improved clinical outcomes” ​of AD seen in the study.

“Improved clinical outcomes of AD means decreasing the rate of progression of the disease through the development of more effective therapies that diminish damage to the CNS. The research summarized in the article suggest that the functional state of the meningeal lymphatics impacts the brain vascular system as well as the degree of CNS neuroinflammation mediated by brain microglia in addition to providing a means to drain potentially harmful macromolecules such as amyloid beta and phospho-tau.”

In the therapeutic experiments summarized in the article, VEGF-C was utilized to help improve lymphatic vascular function and was combined with one of two different monoclonal antibodies recognizing different forms of amyloid beta in order to yield the most efficient amyloid beta removal, said Bolen. 

“In those experiments, VEGF-C was produced through recombinant Adeno-associated virus (AAV) infection of meningeal cells,” ​he added.

Avoiding virus mediated molecule delivery 

In terms of whether there are any limitations or inherent risks involved in this avenue of treating AD though, he said that such an approach for VEGF-C, or any other biologic intended for meningeal lymphatics, would be challenging for patients as immune responses to the AAV would preclude multiple courses of therapy that would likely be required.

“Our current plans do not anticipate requiring virus-mediated delivery of VEGF-C or any other biomolecule in order to effectively rescue dysfunctional meningeal lymphatics,” ​he told BioPharma-Reporter.

Reviewing the progress that PureTech’s meningeal lymphatics research program has made to date, he said the team had prioritized several promising potential therapeutic approaches to modulating meningeal lymphatic drainage.

“Our wholly-owned meningeal lymphatics program in collaboration with the Kipnis lab along with several other prominent academic research labs have made significant strides in our understanding of the functional and anatomical magnitude of the meningeal lymphatic network, its vascular adjacencies and the interplay between these networks with the resident and transitory meningeal immune system.”

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