LONDON – In clinical trials, antiamyloid agents have fallen short as a treatment for Alzheimer’s disease (AD). A group of researchers is taking an alternative approach – human plasma.
It’s still early in the investigation of the approach, but experiments in a mouse model are encouraging, and results of a study of the use of infusions of plasma in patients with mild to moderate AD are expected soon.
This novel approach was described here at the Alzheimer’s Association International Conference (AAIC) 2017.
Fresh Approach
Infusing human blood into patients with dementia makes some sense. There are numerous anecdotes of AD patients who undergo a blood transfusion and subsequently experience improvement in memory that lasts for days.
In addition, a fresh approach to AD therapeutics is desperately needed, Steven Braithwaite, PhD, chief scientific officer, Alkahest, who presented results of a study of the use of plasma infusions in animals at the AAIC, told Medscape Medical News.
Dr Steven Braithwaite
“There have been many approaches to target individual parts of the pathology ― amyloid antibodies, and now tau antibodies ― but is it enough to just target one little piece of the biology? Here, we are able to target a lot more than that,” he said.
Dr Braithwaite was referring to experiments of plasma infusions in immunocompromised mice. Dr Braithwaite and his team first connected the circulatory system of a young mouse to that of an old mouse, a process known as heterochronic parabiosis.
“That provided the first data that showed you could rejuvenate an old mouse by using a young mouse,” said Dr Braithwaite.
The researchers then infused just the soluble components, the plasma, from young mice into old mice and saw similar cognitive improvements.
But mouse plasma is not viable in humans because of immune responses and rejection. Dr Braithwaite’s group took the next step of using young human plasma instead.
For their experiments, the researchers used blood donated by 18-year-olds that was collected by Grifols, a company that that takes whole plasma and fractionates it into its components. These include clotting factor VIII for use in patients with hemophilia and human albumin for volume replacement or correction of hypoalbuminemia.
The optimal age of donors for achieving best cognitive outcomes is still unclear, but age 18 years is generally the youngest age blood donors can be, said Dr Braithwaite.
The mice in the experiments are generally about 1 year old, which, according to Dr Braithwaite, is equivalent to about a person aged 70 to 80 years.
After measuring the speed and distance that the mice moved in an open-field assay, the researchers noted that the mice “acted younger,” said Dr Braithwaite.
Neurogenesis
The changes in behavior exhibited by the mice correlated with histologic changes indicative of neurogenesis.
“Neurogenesis, the generation of new neurons, implies that there are changes in the brain that can overcome the loss of neurons in indications such as Alzheimer’s disease and create a healthier environment for improved brain function,” said Dr Braithwaite.
The mice continued to exhibit these improvements 3 months after they underwent a course of infusion.
It is not clear, however, if the infusions extended life.
“We haven’t looked at how much longer the mice lived, as we are mostly interested in improving quality of life rather than longevity,” said Dr Braithwaite.
The reason this approach works so well likely has something to do with the change in composition of proteins in plasma over time, he said.
Analyses show that with age, about 15% of plasma undergoes significant changes – levels of detrimental factors increase, and levels of beneficial factors decrease, he said.
“Cytokines and other inflammatory molecules go up with age, so perhaps we could reduce some of those, and the growth factors we have in youth go down with age, so maybe we could replenish those to trigger some new regenerative events in the brain.”
Dr Braithwaite pointed out that the protein amyloid beta changes with age and is a hallmark of AD. “So this approach is not too strange a concept.”
Human Trials
It is not the first time researchers in the field of dementia have experimented with human plasma.
A few years ago, researchers tested intravenous immunoglobulin (IVIG), another fraction of plasma, in dementia patients. The rationale was that IVIG would attack foreign proteins.
“They injected antibodies to a whole range of proteins ― the naturally produced immunoglobulin pool,” said Dr Braithwaite.
The experiments were not quite successful.
“There were some hints in those trials, but nothing significant,” said Dr Braithwaite. He added that there was some question of whether the dosing was sufficient and whether other beneficial factors present in plasma may have been missing.
He is more confident about this new approach developed by his company. A test of whole young human plasma infusions has now been completed in humans. The study included 18 patients with mild to moderate AD at Stanford University. The patients received one infusion per week for 4 weeks.
The aim of the trial was to test the safety and tolerability of the infusions. There were also some efficacy endpoints, although Dr Braithwaite stressed that the study was not powered for efficacy.
The study has been submitted for presentation at the Clinical Trials in AD (CTAD) conference, which will be held in November in Boston, Massachusetts, said Dr Braithwaite.
The next step is to identify and then deliver only those proteins that drive function.
“The idea is to actually make protein therapeutics or peptides that will recapitulate that function.”
This, he added, would avoid the need for plasma donors.
Rejuvenating Effect
Other elements of plasma may benefit patients with dementia.
“A disease like Alzheimer’s, or any disease or disorder of aging, is probably multifactorial, so probably involves different mechanisms that go wrong,” said Dr Braithwaite. “An approach where you have multiple proteins, multiple things you can change, may be more effective.”
The company is focusing on about 25 potentially beneficial proteins and on a small molecule that inhibits one of the negative factors. The company is one of the few companies capable of collecting plasma on a scale necessary for such drug development, he said.
Altering proteins and the course of aging might beneficial not just in AD but other in diseases as well, such as Parkinson’s disease “and a whole range of disorders.”
The potential is to change not just cognition, he added.
“Data in the literature from these parabiosis experiments show that you can rejuvenate other organs, like the liver, and muscle, etc, so this could have a systemic rejuvenating effect.”
The consensus view is that 115 to 120 years is “the ultimate lifespan,” said Dr Braithwaite. “So let’s live that life with good quality.”
The concept of using circulating factors to prevent dementia “is becoming more and more accepted” in the field, and reaction to this novel approach among neurologists has been very positive, commented Dr Braithwaite.
“Everybody sees that we need to develop therapeutics for Alzheimer’s disease and we need to do something different, so why not let’s try these different approaches?”
Exciting Possibility
Asked to comment, James Hendrix, PhD, director of global science initiatives at the Alzheimer’s Association, said the emerging research “highlights the exciting possibility of young, healthy human plasma as a source of novel approaches against Alzheimer’s disease.”
Dr Hendrix said these new findings need to be confirmed.
He agreed that plausible next steps include identifying the active component or components in plasma that help protect the brain. “This is so they may be purified and delivered as more traditional therapies ― rather than treating people with undifferentiated blood,” he said.
This would help ensure that treatments are standardized, accessible, and easy to take, he added.
Dr Hendrix reiterated that there is a “desperate need” for new treatments and preventive measures for AD and that scientists need substantially greater support and resources.
“The Alzheimer’s Association is strongly advocating for Congress to continue its commitment to Alzheimer’s and other dementias by increasing funding for research by at least an additional $414 million in fiscal year 2018.”
Dr Braithwaite is an employee of Alkahest. Dr Hendrix has disclosed no relevant relationships.
Alzheimer’s Association International Conference (AAIC) 2017. Abstract 15929, presented Wednesday July 19, 2017.
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