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Pan European Networks: Science & Technology





sing advanced techniques for gene transfer, combined

with materials for cell and tissue engineering, it is

possible to generate an antibody-secreting implant for

passive immunisation. This technology may help to fight against

the deposition of aggregated proteins that accumulate in the

brain, and which are some of the suspected causes of

neurodegeneration. This research highlights the possibilities of

gene and cell therapies to address the treatment of

neurodegenerative diseases including Alzheimer’s.

Neurodegenerative diseases that affect the central nervous

system are among the most important healthcare challenges,

particularly in societies that face a progressive ageing of their

population. Alzheimer’s disease, which is the most common form

of dementia, has dramatic effects on the memory and other

cognitive functions. As the disease advances, the people affected

by Alzheimer’s lose their ability to execute even simple tasks in

their daily life, and experience disorientation and changes in

personality. The supporting families and caregivers face increasing

difficulties to support the life quality of the affected patients. Most

current treatments primarily target the symptoms of the disease

and fail to address its cause. In particular, there is a dramatic lack

of treatments able to slow down the progression of the disease.

Remarkably resilient

The difficulty to design an effective treatment is mainly due to our

poor understanding of the pathologic processes leading to

Alzheimer’s disease. The brain is an incredibly complex and poorly

accessible organ. It is therefore difficult to monitor the changes

that occur during the early stages of disease in the structure and

function of the brain. In addition, the brain is remarkably resilient.

Hence, it is often only when the disease has extensively damaged

neuronal networks that the first symptoms are observed.

In the past few years, remarkable progress has, however, been

made. A constantly increasing number of biomarkers as well as

sophisticated imaging techniques have been developed to

assess disease progression. A recognised feature of Alzheimer’s

disease is the progressive and abnormal accumulation of

misfolded proteins inside the brain. One of the first signs of the

disease is the deposition of the amyloid beta (Aß) peptide both

in blood vessels and inside the brain, forming extracellular

plaques. Later, some neuronal networks also display

neurofibrillary tangles, which are abnormal intraneuronal

deposits of hyperphosphorylated and misfolded forms of another

protein called ‘tau’. Although the exact sequence of events

leading to these pathological manifestations has not been

completely elucidated yet, there is a general assumption that

treatments targeting the Aß and/or tau pathologies may have an

impact on the progression of Alzheimer’s disease.

Immunisation against pathologic proteins as a

treatment for Alzheimer’s disease

At this point, another major question arises: how can we

therapeutically intervene in these pathogenic processes? The

most advanced approach is the development of vaccines or

antibodies able to generate specific immunity against the

abnormal forms of these Aß and tau proteins. Proof-of-concept

studies in preclinical animal models have shown that anti-Aß

antibodies can reduce the amyloid burden in the brain, with a

significant effect on the downstream consequences of this

pathology. These results prompted a series of phase 1-3 clinical

trials in Alzheimer’s patients, which have yielded mixed results,

often considered as disappointing. Nevertheless, the most recent

trials indicate that antibodies against Aß plaques may slow down

disease progression when administered at an early stage of the

disease, in prodromal and mild Alzheimer’s patients. In particular,

recent trials with the antibodies Solanezumab, Crenezumab and

Aducanumab have shown that significant beneficial effects can

be achieved, with a decrease of amyloid plaque deposition and,

more importantly, a slower rate of cognitive decline. However,

these treatments require high-dose bolus injections of

recombinant antibodies every month. This could pose problems if

the treatment needs to be administered for years, even before the

onset of the cognitive impairments.

In order to develop effective therapeutics for the central nervous

system, it is critically important to design technologies to deliver

molecules in the right place at the right time, with minimally

invasive procedures. The delivery of antibodies to the central

nervous system is difficult, because only a small fraction of these

molecules circulating in the blood will penetrate the blood-brain

barrier and reach their target inside the brain. In addition,

immunisation procedures against Aß have caused adverse effects.

Active anti-Aß vaccines led to meningoencephalitis, a major side

effect which has strongly limited this approach. In contrast,

passive immunisation by injection of recombinant anti-Aß

An implantable device that delivers antibodies to target the amyloid

pathology in Alzheimer’s disease