Tag Archives: Drug Target

A new study provides additional evidence that amyloid-beta protein — which is deposited in the form of beta-amyloid plaques in the brains of patients with Alzheimer’s disease — is a normal part of the innate immune system, the body’s first-line defense against infection. The study, published in Science Translational Medicine, finds that expression of human amyloid-beta (A-beta) was protective against potentially lethal infections in mice, in roundworms and in cultured human brain cells. The findings may lead to potential new therapeutic strategies and suggest limitations to therapies designed to eliminate amyloid plaques from patient’s brains.

“Neurodegeneration in Alzheimer’s disease has been thought to be caused by the abnormal behavior of A-beta molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients’ brains,” says Robert Moir, MD, of the Genetics and Aging Research Unit in the Massachusetts General Hospital (MGH) Institute for Neurodegenerative Disease (MGH-MIND), co-corresponding author of the paper. “This widely held view has guided therapeutic strategies and drug development for more than 30 years, but our findings suggest that this view is incomplete.”

A 2010 study co-led by Moir and Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging unit and co-corresponding author of the current study, grew out of Moir’s observation that A-beta had many of the qualities of an antimicrobial peptide (AMP), a small innate immune system protein that defends against a wide range of pathogens. That study compared synthetic forms of A-beta with a known AMP called LL-37 and found that A-beta inhibited the growth of several important pathogens, sometimes as well or better than LL-37. A-beta from the brains of Alzheimer’s patients also suppressed the growth of cultured Candida yeast in that study, and subsequently other groups have documented synthetic A-beta’s action against influenza and herpes viruses.

The current study is the first to investigate the antimicrobial action of human A-beta in living models. The investigators first found that transgenic mice that express human A-beta survived significantly longer after the induction of Salmonella infection in their brains than did mice with no genetic alteration. Mice lacking the amyloid precursor protein died even more rapidly. Transgenic A-beta expression also appeared to protect C.elegans roundworms from either Candida or Salmonella infection. Similarly, human A-beta expression protected cultured neuronal cells from Candida. In fact, human A-beta expressed by living cells appears to be 1,000 times more potent against infection than does the synthetic A-beta used in previous studies.

That superiority appears to relate to properties of A-beta that have been considered part of Alzheimer’s disease pathology — the propensity of small molecules to combine into what are called oligomers and then aggregate into beta-amyloid plaques. While AMPs fight infection through several mechanisms, a fundamental process involves forming oligomers that bind to microbial surfaces and then clump together into aggregates that both prevent the pathogens from attaching to host cells and allow the AMPs to kill microbes by disrupting their cellular membranes. The synthetic A-beta preparations used in earlier studies did not include oligomers; but in the current study, oligomeric human A-beta not only showed an even stronger antimicrobial activity, its aggregation into the sorts of fibrils that form beta-amyloid plaques was seen to entrap microbes in both mouse and roundworm models.

Tanzi explains, “AMPs are known to play a role in the pathologies of a broad range of major and minor inflammatory disease; for example, LL-37, which has been our model for A-beta’s antimicrobial activities, has been implicated in several late-life diseases, including rheumatoid arthritis, lupus and atherosclerosis. The sort of dysregulation of AMP activity that can cause sustained inflammation in those conditions could contribute to the neurodegenerative actions of A-beta in Alzheimer’s disease.”

Moir adds, “Our findings raise the intriguing possibility that Alzheimer’s pathology may arise when the brain perceives itself to be under attack from invading pathogens, although further study will be required to determine whether or not a bona fide infection is involved. It does appear likely that the inflammatory pathways of the innate immune system could be potential treatment targets. If validated, our data also warrant the need for caution with therapies aimed at totally removing beta-amyloid plaques. Amyloid-based therapies aimed at dialing down but not wiping out beta-amyloid in the brain might be a better strategy.”

Says Tanzi, “While our data all involve experimental models, the important next step is to search for microbes in the brains of Alzheimer’s patients that may have triggered amyloid deposition as a protective response, later leading to nerve cell death and dementia. If we can identify the culprits — be they bacteria, viruses, or yeast — we may be able to therapeutically target them for primary prevention of the disease.”

Paper: “Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease”
Reprinted from materials provided by Massachusetts General Hospital.

Researchers have shown how brain connections, or synapses, are lost early in Alzheimer’s disease and demonstrated that the process starts — and could potentially be halted — before telltale plaques accumulate in the brain. Their work, published online by Science, suggests new therapeutic targets to preserve cognitive function early in Alzheimer’s disease.

The researchers show in multiple Alzheimer’s mouse models that mechanisms similar to those used to “prune” excess synapses in the healthy developing brain are wrongly activated later in life. By blocking these mechanisms, they were able to reduce synapse loss in the mice.

Currently, there are five FDA-approved drugs for Alzheimer’s, but these only boost cognition temporarily and do not address the root causes of cognitive impairment in Alzheimer’s. Many newer drugs in the pipeline seek to eliminate amyloid plaque deposits or reduce inflammation in the brain, but the new research from Boston Children’s suggests that Alzheimer’s could be targeted much earlier, before these pathologic changes occur.

“Synapse loss is a strong correlate of cognitive decline,” says Beth Stevens, assistant professor in the Department of Neurology at Boston Children’s, senior investigator on the study and a recent recipient of the MacArthur “genius” grant. “We’re trying to go back to the very beginning and see how synapse loss starts.”

The researchers looked at Alzheimer’s — a disease of aging — through an unusual lens: normal brain development in infancy and childhood. Through years of research, the Stevens lab has shown that normal developing brains have a process to “prune” synapses that aren’t needed as they build their circuitry.

“Understanding a normal developmental process deeply has provided us with novel insight into how to protect synapses in Alzheimer’s and potentially a host of other diseases,” says Stevens, noting that synapse loss also occurs in frontotemporal dementia, Huntington’s disease, schizophrenia, glaucoma and other conditions.

In the Alzheimer’s mouse models, the team showed that synapse loss requires the activation of a protein called C1q, which “tags” synapses for elimination. Immune cells in the brain called microglia then “eat” the synapses — similar to what occurs during normal brain development. In the mice, C1q became more abundant around vulnerable synapses before amyloid plaque deposits could be observed.

When Stevens and colleagues blocked C1q, a downstream protein called C3, or the C3 receptor on microglia, synapse loss did not occur.

“Microglia and complement are already known to be involved in Alzheimer’s disease, but they have been largely regarded as a secondary event related to plaque-related neuroinflammation, a prominent feature in progressed stages of Alzheimer’s,” notes Soyon Hong, the Science paper’s first author. “Our study challenges this view and provides evidence that complement and microglia are involved much earlier in the disease process, when synapses are already vulnerable, and could potentially be targeted to preserve synaptic health.”

A human form of the antibody Stevens and Hong used to block C1q, known as ANX-005, is in early therapeutic development with Annexon Biosciences (San Francisco) and is being advanced into the clinic. The researchers believe it has potential to be used someday to protect against synapse loss in a variety of neurodegenerative diseases.

“One of the things this study highlights is the need to look for biomarkers for synapse loss and dysfunction,” says Hong. “As in cancer, if you treat people at a later stage of Alzheimer’s, it may already be too late.”

The researchers also found that the beta-amyloid protein, C1q and microglia work together to cause synapse loss in the early stages of Alzheimer’s. The oligomeric form of beta-amyloid (multiple units of beta-amyloid strung together) is already known to be toxic to synapses even before it forms plaque deposits, but the study showed that C1q is necessary for this effect. The converse was also true: microglia engulfed synapses only when oligomeric beta-amyloid was present.

Source: Reprinted from materials provided by Boston Children’s Hospital
Paper: “Complement and microglia mediate early synapse loss in Alzheimer mouse models”

The European Medicines Agency (EMA) has released draft revised guidelines on medicines for the treatment of Alzheimer’s disease and other types of dementias for a six-month public consultation.

EMA follows a multi-stakeholder approach to facilitate research and development of more effective medicines. The revised guidelines take into account comments received at EMA’s workshop on the clinical investigation of medicines for the treatment of Alzheimer’s disease in November 2014. This workshop brought together a wide range of stakeholders, including patient representatives, regulators, pharmaceutical industry and independent experts. The aim of the workshop was to ensure that during the revision of its guidelines, EMA would be able to consider the most up-to-date scientific developments in understanding and treating Alzheimer’s disease and views from experts in the field. The revised guidelines also build on EMA scientific advice provided for a number of specific development plans for Alzheimer’s disease in recent years, as well as the qualification of several biomarkers for the selection of patients in clinical trials.

The revised guideline specifically addresses the:

impact of new diagnostic criteria for Alzheimer’s disease, including early and even asymptomatic disease stages, on clinical trial design
choice of parameters to measure trial outcomes and the need for distinct assessment tools for the different disease stagesin Alzheimer’s (different signs and symptoms, differences in changes over time, severity)
potential use of biomarkers and their temporal relationship with the different phases of Alzheimer’s disease at different stages of medicine development (mechanism of action, use as diagnostic test, enrichment of study populations, stratification of subgroups, safety and efficacy markers etc.)
design of long-term efficacy and safety studies

Comments received during the consultation will be taken into account in the finalisation of the guideline.

Stakeholders are invited to send their comments by 31 July 2016. To learn more, visit the EMA website.

Source: EMA

The Innovative Medicines Initiative (IMI) has launched a new call for research proposals that will aim to accelerate the development of medicines in a number of key areas, including neurological disorders.

The Alzheimer’s disease and Parkinson’s disease topic of the call focuses on better understanding how the protein tangles found in both diseases spread through the brain, with the ultimate goal of establishing new drug targets.

The IMI initiative, a partnership between the European Union and the pharmaceutical industry association EFPIA, aims to stimulate the development of safer and more effective medicines.

Other topics in the call, known as IMI 2 – Call 7, include safety, pain, cancer, eye diseases, and big data. Call 7 has a budget of €46.8 million from IMI, which will be matched by €46.8 million from the EFPIA companies in the projects. The submission deadline for this call is March 17, 2016.

IMI simultaneously launched a second call, known as IMI 2 – Call 8, for research proposals on Ebola and related diseases.

Visit the IMI website to learn more about the call topics and to apply.

‘Seeding’ property provides new focus for treatment to delay progression of disorder

By identifying in spinal fluid how the characteristic mutant proteins of Huntington’s disease spread from cell to cell, researchers have created a new method to quickly and accurately track the presence and proliferation of these neuron-damaging compounds — a discovery that may accelerate the development of new drugs to treat this incurable disease.

The researchers added that the cell-to-cell “seeding” property of these mutant proteins seems to be a critical part of the disease’s progression. Their findings also advance a new drug-discovery approach: stopping the cellular transfer of the seeding compounds. Study results appear online in the journal “Molecular Psychiatry”.

New research highlights how nerves – whether harmed by disease or traumatic injury – start to die, a discovery that unveils novel targets for developing drugs to slow or halt peripheral neuropathies and devastating neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

Peripheral neuropathy damages nerves in the body’s extremities and can cause unrelenting pain, stinging, burning, itching and sensitivity to touch. The condition is commonly associated with diabetes or develops as a side effect of chemotherapy.

Nerve cells talk to each other by transmitting signals along communication cables called axons. Such signals underlie vital activities, such as thinking and memory, movement and language. As part of the study, the researchers showed they could prevent axons from dying, a finding that suggests therapies could be developed to counteract the withering away of nerve axons.

The research, by scientists at Washington University School of Medicine in St. Louis, is reported online April 23 in the journal Science.

“We have uncovered new details that let us piece together a major pathway involved in axon degeneration,” said senior author Jeffrey Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. “This is an important step forward and helps to identify new therapeutic targets. That we were able to block axon degeneration in the lab also gives us hope that drugs could be developed to treat patients suffering from a variety of neurological conditions.”

A common thread among many neurological disorders and traumatic nerve injuries is the degeneration of axons, which interrupts nerve signaling and prevents nerves from communicating with one another. Axon degeneration is thought to be an initiating event in many of these disorders. In fact, an unhealthy axon is known to trigger its own death, and researchers are keenly interested in understanding how this happens.

Working in cell cultures, fruit flies and mice, Milbrandt and co-author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology, and their colleagues showed that a protein already known to be involved in axon degeneration, acts like a switch to trigger axon degeneration after an injury.

Moreover, they found that this protein, once unleashed, causes a rapid decline in the energy supply within axons. Within minutes after the protein – called SARM1 – is activated in neurons, a massive loss of nicotinamide adenine dinucleotide (NAD), a chemical central to a cell’s energy production, occurs within the axon.

Source: News-Medical.net

The Dementia Discovery Fund, which is being established by the UK government with initial commitments totalling $100 million, brings together leading pharmaceutical companies, the UK government and Alzheimer’s Research UK to address the rising threat posed by dementia by supporting research into future treatments.

The fund aims to identify and nurture promising new avenues of research from around the world in the field of dementia. It is hoped that by providing critical financial support and expert advice during the early stages of research, the development of innovative new treatments for this disease could be accelerated.

The Dementia Discovery Fund will be structured as a typical venture capital fund, but will be the first to focus solely on dementia research. The Fund will comb the global research community for the most promising early stage research to invest in. A scientific advisory board of representatives from each of the partner organisations will provide expert scientific input during the selection of research programmes, as well as providing ongoing advice during pre-clinical and early clinical development. Partners will then be sought for the progression of promising assets through the clinical development pipeline, the intention being that proceeds from licensing or sale of such programmes will be returned to the Fund and its investors. The Fund will appoint a professional investment manager in due course, which will be responsible for its financial governance and investment decisions.

Source: Reuters

Belgian scientists have completed a study, reprogramming skin cells from three dementia patients into induced pluripotent stem cells (iPSCs) – immature cells that mimic stem cells taken from early-stage embryos. Their findings, which revealed a signalling pathway linked to frontotemporal dementia (FTD), are published in the January 13th 2015 edition of the journal, Stem Cell Reports.

Prof. Philip Van Damme, from the Leuven Research Institute for Neuroscience and Disease in Belgium, said: “Our findings suggest that signalling events required for neurodevelopment may also play major roles in neurodegeneration.

Treatment with a drug that suppressed the pathway, known as “Wnt”, restored the ability of neurons affected by the disease to develop normally. “Targeting such pathways…may result in the creation of novel therapeutic approaches for frontotemporal dementia”, Prof. Van Damme said.

The researchers found that iPSCs derived from the patients’ cells were unable to generate cortical neurons, the cell type most affected by FTD. Cortical neurons are the cells responsible for most of the brain’s complex higher activity enabling thought, perception and voluntary movement.

Co-author Dr Catherine Verfaillie, from the University of Leuven in Belgium commented that IPSC models could now be used to better understand dementia, and in particular FTD, which accounts for about half of dementia cases before the age of 60.

Source: Alzheimer Europe

Pharmaceutical companies, AstraZeneca and Eli Lilly and Co (Lilly) announced on 16 September having reached an agreement to jointly develop and commercialise AZD3293, an oral BACE inhibitor currently in development as a potential treatment for Alzheimer’s disease (AD).

In Phase I studies, AZD3293 had been shown to significantly and dose-dependently reduce levels of amyloid beta in the cerebro-spinal fluid of trial participants with Alzheimer’s disease as well as in healthy volunteers. AstraZeneca announced its plan to move AZD3293 into registration trials earlier this year.

This alliance has been formed with the aim of progressing AZD3293 rapidly into a Phase II/III clinical trial in patients with early Alzheimer’s disease.

Lilly will lead clinical development, working with researchers from AstraZeneca’s Innovative Medicines Unit for neuroscience, while AstraZeneca will be responsible for manufacturing. The companies will take joint responsibility for the commercialisation of AZD3293.