Breaking Down Barriers: Towards Gene-Targeting Drugs for Brain Diseases

The human brain is a complex and intricate organ that has long been a challenge to treat when it comes to diseases like Alzheimer’s, Parkinson’s, and brain cancers. One of the major obstacles in delivering therapeutic drugs to the brain is the blood-brain barrier (BBB), a protective layer that restricts the passage of molecules from the bloodstream into the brain.

To overcome this hurdle, researchers at Tokyo University of Science have been exploring new ways to deliver gene-targeting drugs, specifically antisense oligonucleotides (ASOs) and heteroduplex oligonucleotides (HDOs), directly to the brain. In a recent study published in the Journal of Controlled Release, the team led by Professor Makiya Nishikawa demonstrated that modifying HDOs with cholesterol molecules (Chol-HDOs) could improve their stability and specificity, allowing them to penetrate the cerebral cortex beyond the blood vessels.

The key to this success lies in how Chol-HDOs interact with proteins in the bloodstream. Unlike ASOs and HDOs, which bind electrostatically to serum proteins with low affinity and are taken up by cells, Chol-HDOs bind tightly to serum proteins, including lipoproteins, via hydrophobic interactions. This strong binding results in slow clearance from the bloodstream, allowing Chol-HDOs to remain in circulation for a longer period.

The researchers also showed that inhibiting scavenger receptors in cells reduces the uptake of both ASOs and Chol-HDOs in the liver and kidneys, shedding light on how these compounds are taken up by different organs. This finding has significant implications for the design of brain-targeting drugs based on Chol-HDOs.

With over 55 million people living with dementia worldwide and 300,000 cases of brain cancer reported annually, the potential therapeutic applications of modified HDOs are vast. The possibility of efficiently delivering ASOs and other nucleic acid-based drugs to the brain may lead to the development of treatments for brain diseases with significant unmet medical needs.

This study provides valuable insight into how brain-targeting drugs could be designed based on Chol-HDOs, paving the way for a new generation of compounds that effectively target brain diseases. As research continues, we can expect modified HDOs to offer hope to millions of patients and their families around the world.

The world of medicine is abuzz with a groundbreaking discovery that challenges the long-held assumption about the genetic marker FOXR2. For years, physicians have relied on this marker to diagnose central nervous system (CNS) neuroblastoma, a type of brain tumor. However, new research from St. Jude Children’s Research Hospital reveals that FOXR2 activation is not exclusive to CNS neuroblastoma. In fact, it was found in multiple pediatric CNS tumor types, including brain tumors, with significantly different clinical outcomes.

According to Dr. Jason Cheng-Hsuan Chiang, corresponding author of the study, “People have been using FOXR2 activation as a clinical diagnostic for CNS neuroblastoma. But we unexpectedly saw it in a patient’s recurrent non-neuroblastoma tumor, which motivated us to look into other brain tumors.” The researchers used data from the St. Jude Cloud, a vast repository of genomic and sequencing data from St. Jude patients, to identify 42 tumors with activated FOXR2 in 41 patients.

The findings were published today in Neuro-Oncology, a journal of the Society for Neuro-Oncology. “When we looked at the clinical outcomes of the different types of tumors with FOXR2 activation, there was a pretty stark difference,” said co-first author Emily Hanzlik, MD. “The CNS neuroblastomas had an exceptionally good outcome when they were treated with multimodal therapy, whereas the other types of tumors in the cohort, the high-grade gliomas and the pineoblastomas, had pretty dismal outcomes.”

This study highlights the importance of combining molecular findings like DNA and RNA sequencing, histology, and imaging to correctly understand a specific brain tumor. “Only with a holistic view can we choose the best treatment approach for that patient,” Dr. Chiang emphasized.

The discovery of undetected mechanisms of FOXR2 activation in multiple brain tumor types has significant implications for diagnosis, prognosis, and treatment. As Dr. Alexa Siskar, co-first author, noted, “Now that we described these genomic events, hopefully, others will be able to detect them in their patients as well.” This breakthrough opens up new avenues for research and care, ultimately leading to better outcomes for brain tumor patients.

The study, led by researchers at NYU Langone Health and its Perlmutter Cancer Center, has made a groundbreaking discovery that could change the way melanoma is diagnosed and treated. The researchers have found that monitoring blood levels of DNA fragments shed by dying tumor cells may accurately predict skin cancer recurrence in stage III melanoma patients.

The study showed that approximately 80% of stage III melanoma patients who had detectable levels of circulating tumor DNA (ctDNA) before they started treatment to suppress their tumors went on to experience recurrence. The researchers also found that the disease returned more than four times faster in this group than in those with no detectable levels of the biomarker, and the higher their levels, the faster cancer returned.

“Our findings suggest that circulating tumor DNA tests could help oncologists identify which melanoma patients are most likely to respond well to therapy,” said study lead author Mahrukh Syeda. “In the future, such assessments may be used routinely in the clinic to help guide treatment decisions.”

The research team also found that nearly all of those with detectable levels of ctDNA at three, six, nine, or 12 months into treatment experienced melanoma recurrence. This suggests that if the gene fragments are not observable prior to therapy but appear later on, this could indicate that the disease might be worsening.

The study’s senior author, David Polsky, notes that in some cases, cancer still recurred even though the patient had received a negative ctDNA test before starting therapy. To address this, the authors next plan to improve the sensitivity of their test and explore whether using the biomarker to make treatment decisions can indeed improve patients’ chances of survival and quality of life.

The study’s findings have significant implications for melanoma patients and could potentially save lives by providing early feedback on treatment progress and cancer growth. The researchers are now planning to further investigate the use of ctDNA tests in clinical settings, which could lead to more targeted and effective treatments for this aggressive form of skin cancer.