Beyond Antibody Therapies: Novel Therapeutic Approaches to Combat Alzheimer’s Disease
by Nicole Koutsodendris | February 6, 2024
Alzheimer’s disease (AD) is a neurological disorder that affects nearly 6.7 million Americans over the age of 65. The widespread nature of this disease means that many people are impacted by it in some way, whether it is being diagnosed with the disorder, or caring for an afflicted friend or family member. Despite its high prevalence, there have been limited treatment options available to AD patients for the past several decades. Recent advancements have led to the exciting development of antibody therapies to target the disease; however, these therapies have some limitations and may potentially lead to severe side effects. Innovative therapies targeting RNA represent the new frontier of therapeutic development for AD and have the potential to provide longer-lasting effects that may further delay the disease progression of AD.
Biological Hallmarks and Symptomatic Treatment of AD
AD is a type of dementia that involves progressive memory loss and cognitive decline. These symptoms are a result of neuronal death and loss of brain tissue over time. While there are a variety of genetic and environmental factors that can lead to the disease, all AD patients exhibit specific biomarkers that are used for diagnosis. The two major biomarkers of AD include amyloid-beta plaques and neurofibrillary tangles, which are toxic aggregates of amyloid and tau proteins, respectively. These toxic protein aggregates accumulate within and outside neurons, disrupt normal cellular functions, and lead to neuronal dysfunction and death.
For several decades, the only available treatment options for AD patients focused on alleviating symptoms without effectively addressing the underlying biology of the disease. Acetylcholinesterase inhibitors and Memantine are drugs that work to alter the levels of neurotransmitters in the brain, which are the molecules neurons use for communication. While these drugs may temporarily reduce symptoms, such as decreasing agitation, anxiety, and delusions, they do not delay disease progression or reduce memory loss.
Current State of Antibody Therapies to Treat AD
Decades of rigorous scientific research led to important discoveries that have deepened our understanding of the underlying biology of AD. Many studies have shown that amyloid plaques are toxic and lead to neural dysfunction and death. Preclinical proof-of-concept studies showed that the removal of amyloid plaques may reduce AD-related pathology and slow the progression of the disease, supporting the amyloid hypothesis of AD. Consequently, several different companies developed antibodies designed to target and remove amyloid beta protein fragments. Several years ago, human clinical trials began to test the effectiveness of these anti-amyloid therapies in combating AD. Two drugs showed profound amyloid plaque clearance in clinical trials, leading to FDA approval of anti-amyloid drugs, aducanumab and lecanemab.
These anti-amyloid drugs utilize passive immunization with antibodies that are designed to bind either amyloid peptides (aducanumab) or aggregated amyloid protein (lecanemab), enhancing the clearance of amyloid from the central nervous system. Therefore, these drugs significantly reduce the burden of amyloid plaques within the brain. These anti-amyloid monoclonal antibodies both led to a ~30% reduction in cognitive decline during the trial period compared to the placebo. Furthermore, lecanemab delayed disease progression from mild to severe dementia by approximately 7.5 months and simulation modeling suggests that it can extend mild dementia by 2.5 years. These results are immensely encouraging since previous treatments were unable to delay disease progression. Additionally, these drugs are likely to significantly reduce the emotional and financial burdens of caregivers.
The development and approval of anti-amyloid drugs represent a landmark achievement in Alzheimer’s therapeutics, offering much-needed hope for patients struggling with the disease. Still, there are several limitations to anti-amyloid therapeutics to consider. In a small portion of patients, anti-amyloid drugs may lead to a serious side effect known as amyloid-related imaging abnormalities, or ARIA, which results in severe inflammation and swelling of the brain. During the phase III clinical trial for lecanemab, one patient undergoing treatment died from ARIA, highlighting the potentially-fatal side effect of amyloid antibody treatments and sparking conversations on how to mitigate this in future patients. These treatments also involve multiple infusions at a high cost, leading some analysts to consider the therapeutic benefits of anti-amyloid treatments to be somewhat limited, based on estimated quality adjusted life-years.
With the FDA approval and availability of antibody therapies targeting amyloid, there is now a sense of optimism and relief that Alzheimer’s patients will have additional therapeutic options at their disposal. Nevertheless, researchers remain persistent in continuing to develop novel therapeutics that have the potential to provide even more pronounced and longer-lasting therapeutic benefits for AD patients than currently available antibody treatments.
Development of Novel RNA Therapeutics to Treat Alzheimer’s Disease
The next frontier of treatments for AD include methods that target the earlier forms of amyloid and tau before they develop into toxic protein aggregates. These therapies target the mRNA, which are the building blocks that ultimately encode for the protein. Reducing mRNA limits the amount of protein that is being produced and could hinder the damage of toxic protein aggregates by preventing their formation in the first place.
RNA therapies are a newer class of therapies that are being investigated for their potential to treat AD and other disorders. These RNA therapies include anti-sense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), which are short strands of oligonucleotides that can be specifically designed to reduce the mRNA of a particular target of interest. These RNA therapies differ in their structure and mechanism of action, as ASOs are single-stranded oligonucleotides that modulate the expression of target RNAs while siRNAs are double-stranded RNA complexes that lead to the degradation of target mRNA. These minor differences in structure lead to slight differences in their targeting location of mRNA, cost of treatment, and simplicity of treatment development.
Since ASOs and siRNAs target the original source of the protein pathogenesis, they have a higher chance of reducing overall protein load downstream. Preclinical studies of ASOs have shown that they can be used to target amyloid or tau mRNA and provide significant reduction of neuronal and tissue loss. Similarly, preclinical studies using cellular and mouse models of AD show that siRNAs targeting amyloid and tau mRNA can reduce the development of both these protein pathologies. These preclinical models show the siRNAs do not induce neurotoxicity or neuroinflammation, so the brain swelling that occurs with antibody therapies may not be an issue with RNA therapies. “There’s good reason to think that RNA based therapies that reduce levels of “toxic” gene products will find a place in neurodegenerative diseases, including the dementias”, says Dr. Henry Paulson, who is the senior author on a study that optimized the development of siRNAs to target tau and amyloid precursor protein. “Companies are continuing to produce improved RNA reagents that are likely to be safer and more stable. I remain optimistic!”
So far, phase 1 human clinical trials recently concluded testing tau-targeting ASOs and there were no severe adverse events that occurred during the 13-week treatment period, indicating that they are a relatively safe treatment option. Excitingly, the patients that received the tau-targeting ASOs also displayed a considerable 50% reduction in total tau in their cerebrospinal fluid 24 weeks post-last dose than the patients that received the placebo.
Lead author of the publication outlining the results of this tau-targeting ASO clinical trial, Dr. Catherine Mummery, states, “this trial is the first time we have assessed a genetic therapy in AD. The phase I results of this antisense oligonucleotide targeting the MAPT gene have shown the drug is safe, and critically that it shows target engagement, reducing levels of tau in the spinal fluid and lowering tau burden on tau PET, the first anti tau drug to successfully lower levels of tau. The larger phase II trial aims to confirm these findings and determine whether this can lead to slowing of cognitive decline”. These encouraging results indicate that RNA therapies targeting tau hold potential for being viable and safe therapeutic options for Alzheimer’s disease.
Comparison of Antibody vs. RNA Therapies to Combat AD
There are key differences between the most recently approved antibody therapies to treat Alzheimer’s and the new class of RNA therapies that are undergoing clinical development and testing that are worth considering. Namely, antibody and RNA therapies differ in the ease of cost and manufacturing, durability of therapeutic effects, and magnitude of effects.
First of all, antibody and RNA therapies differ in their ease and cost of production. The manufacturing process for antibody treatments is time-consuming and costly. This compels companies to set higher prices for these therapies, making them inaccessible for some patients. The anti-amyloid therapy aducanumab requires a monthly infusion at a titer of 10mg/kg by the seventh infusion, at a cost of $28,200 annually for each patient. This means high production needs for the manufacturing company and high cost for patients. Reports suggest that ASOs and siRNAs have less complex manufacturing procedures and can potentially be offered at lower costs to patients.
Furthermore, antibody and RNA therapies differ in the durability of their therapeutic effects. Anti-amyloid therapies involve the infusion of antibodies that bind to existing aggregated amyloid and help clear it from the brain. However, additional amyloid aggregates continue to be produced after the infusion, and therefore, patients need infusions of the antibodies every 4 weeks to maintain low levels of amyloid protein. This makes the frequency of administration often and durability of therapeutic effects relatively short-lived. On the other hand, ASOs and siRNAs target the mRNA, which is upstream of protein production. Since these RNA therapies are targeting the building blocks of protein, they can help prevent the formation of additional protein aggregates. This means that these RNA therapies may have longer-lasting therapeutic effects, as one study on tau-targeting ASOs showed that tau levels remained low even 12 weeks after the initial infusion in mice. These longer-lasting effects of RNA therapies mean fewer infusions, and as a result, likely mean reduced cost compared to antibody therapies.
Finally, antibody and RNA therapies differ in their magnitude of therapeutic effects. Results from the anti-amyloid clinical trials indicate that they delayed disease progression by 6 months in AD patients. While this delay in progression is optimistic for patients that previously had few treatment options available to them, there is still room for improvement for a therapy to provide an even stronger effect on delaying disease progression. Since ASOs and siRNAS target the mRNA before the toxic protein aggregates build-up, it’s likely that they will be even more effective at reducing pathologies and delaying disease progression, although future clinical trials will show whether this is the case.
Dr. Catherine Mummery reflects on the current state of RNA therapeutics, stating “genetic therapies have huge potential and have already dramatically altered the course and management of other neurodegenerative diseases, such as Spinal Muscular Atrophy. If we can harness that impact in dementias like Alzheimer’s disease, treatment could potentially not just slow the course of the disease a little, but could feasibly dramatically slow or even halt progression. That is a way off, but is tremendously exciting for the field”.
In conclusion, it’s an exhilarating time for research and treatment development for Alzheimer’s disease. Our deeper understanding of the underlying biology of the disease is paving the way to more targeting therapies that are providing more meaningful therapeutic benefits for patients. Recent breakthroughs in antibody therapies have provided hope and options for patients and their caregivers. It is important to keep in mind that while these anti-amyloid therapies are only able to delay the inevitable and slow disease progression by 7.5 months, there are countless spouses and children that would give anything to have just a few more “good” months with their loved ones. Building upon the newfound hope and success offered by anti-amyloid therapies, the next frontier of AD therapeutics shows that RNA therapeutics are a promising and innovative option that may provide even more therapeutic benefits and will hopefully provide caregivers even more “good” months, and even years, with their loved ones.