More than 5 million people in the United States and an estimated 50 million people worldwide are living with Alzheimer’s disease. More than 10 million people worldwide are living with Parkinson’s. Brain tumors and tumors of the central nervous system are the most common form of cancer in children under 19 and the leading cause of cancer-related deaths in children under 14 in the U.S. While antibody drugs have made great strides in cancer therapies, crossing the blood-brain barrier (BBB) and ensuring proper clearance from the brain have hindered the use of antibody drugs for the treatment of neurological diseases.
Aptamers can potentially meet a critical unmet need for therapeutics addressing neurological disease. Due to their small size, aptamers can better penetrate tissues, cells, and the blood-brain barrier. They are intrinsically non-immunogenic and chemically synthesized, eliminating concerns regarding biological contamination or long-term reagent supply often associated with antibodies. Though there is risk associated with the pursuit of novel drug therapies, there is huge potential for pharmaceutical sales, increased survival rates, reduced health care costs, and enhanced quality of life.1,2,3,6,9
PDGFRβ Targeting in Glioblastoma
A team of researchers from Italy and Luxembourg developed an aptamer-drug conjugate that penetrates the blood-brain barrier for the treatment of glioblastoma. Due to expression of PDGFRβ on tumorigenic glioblastoma stem cells and resistant glioblastomas, an anti-PDGFRβ aptamer was selected for targeting. Drug was entrapped in the lipophilic portion of biodegradable polymeric nanoparticles (PNPs). RNA aptamer to PDGFRβ was then conjugated to the PNPs. Entrapment of the low solubility drug candidate in the PNPs increased its bioavailability, resulting in a 1,000-fold increase in cytotoxicity compared to the free drug. Aptamer-PNPs crossed the blood-brain barrier and accumulated at the tumor site. In vivo studies demonstrated speciﬁc glioblastoma tumor uptake and reduction in tumor marker expression in cancer-bearing mice following five days of daily intravenous administration.5
Protection Against Acute Stroke
Toll-like receptor 4 (TLR4) is a key player in the adaptive immune response. It is involved in several pathologies including stroke, myocardial infarction, atherosclerosis, sepsis, multiple sclerosis, and chronic pain. Researchers in Spain have investigated TLR4-blocking DNA aptamers specifically for stroke treatment. The selected aptamer inhibited activity in both LPS-stimulated HEK-blue-hTLR4 cells and peritoneal macrophages stimulated with LPS. In in vivo studies involving mice and rats subjected to permanent middle cerebral artery occlusion (pMCAO), the TLR4-blocking aptamer reduced ischemic brain injury when administered 4 or 6 hours after injury, the typical time frame for administration of stroke treatment. Imaging studies showed aptamer presence in the blood and in the brain. Continued protective effects were observed at the final 21-day time point. While stroke treatment with tissue plasminogen activator, tPA, is a valid option in only 5% of cases, TLR4-blocking aptamers are a promising, non-toxic alternative.4
The aggregation of α-synuclein protein in neurons has been implicated in the pathogenesis of Parkinson’s Disease. While anti-α-synuclein antibody treatment has shown some success, antibody-based immunotherapy is limited by the inherent immunogenicity of antibodies and the inability of antibodies to access intracellular targets. Aptamer-based immunotherapy is an attractive alternative. Researchers in China have reported preliminary results for a selective aptamer to α-synuclein. In vitro, the aptamer inhibited α-synuclein aggregation and association with mitochondria. It also promoted intracellular α-synuclein degradation and preserved neuron viability in the presence of α-synuclein over-expression.In vivo, the α-synuclein aptamer could potentially prevent α-synuclein aggregation, promote the clearance of existing aggregates, and reduce toxic effects of α-synuclein aggregates on neurons.8
Treating Alzheimer’s and Dementia
Autoimmunity and autoantibodies have been implicated in the pathogenesis of a growing number of disorders. A research team in Germany recently confirmed the presence of functional autoantibodies against G-protein coupled receptors in serum from patients with Alzheimer’s and vascular dementia. Based on binding and epitope-mapping studies, aptamer BC007 with selectivity for the GPCR-AAB FAB fragment was developed as a “broad spectrum neutralizer”. When tested in a bioassay consisting of spontaneously beating cultured neonatal rat cardiomyocytes, aptamer BC007 completely neutralized function of the GPCR-AABs. Successful in vitro neutralization suggests potential utility of the BC007 aptamer as an in vivo treatment for dementia patients.7
Selection of Therapeutic Aptamers
Base Pair has years of experience performing multiplex selection of aptamers to a wide range of targets, including circulating proteins, cell surface markers, and small molecules, including opioids and opioid metabolites. We have also selected for aptamers that enter specific cells of interest. Selecting aptamers to several related targets in a single project using Base Pair’s patented multiplex SELEX technology can increase chances of success and reduce time to market with new therapeutics. Contact Base Pair today to learn more about aptamer development for therapeutics.
- Alzheimer’s Association. https://www.alz.org/alzheimers-dementia/facts-figures. Accessed Feb 22, 2019.
- Alzheimer’s Disease International. https://www.alz.co.uk/research/statistics. Accessed Feb 22, 2019
- Brain Tumors By the Numbers. https://events.braintumor.org/wp-content/uploads/2016/03/BrainTumorsBytheNumbers_12.04.15.pdf. Accessed Feb 22, 2019.
- Fernandez, G. et al. TLR4-binding DNA aptamers show a protective effect against acute stroke in animal models. Molecular Therapy. 2018. https://doi.org/10.2016/j.ymthe.2018.05.019
- Monaco, I., et al. Aptamer functionalization of nanosystems for glioblastoma targeting through the blood-brain barrier. Journal of Medicinal Chemistry. 60:4510-4516. 2017.
- Parkinson’s Foundation. https://parkinson.org/Understanding-Parkinsons/Statistics. Accessed February 22, 2019.
- Walukat, G., et al. Functional autoantibodies in patients with different forms of dementia. PLoS One. 2018. 13(3):e0192778.
- Zheng, Y., et al. Novel DNA aptamers for parkinson’s disease treatment inhibit a-synuclein aggregation and facilitate its degradation. Molecular Therapy Nucleic Acids. 2018. 11:228-242.
- Wen, J., et al. A unique aptamer-drug conjugate for targeted therapy of multiple myeloma. Leukemia. 2016. 30: 987–991.