Peptide successfully delivered siRNA across the blood-brain barrier to treat stroke

Peptide successfully delivered siRNA across the blood-brain barrier to treat stroke.  New breakthrough in RNAi therapy: peptide successfully delivered siRNA across the blood-brain barrier to treat stroke. 

Oxidative stress plays a key role in neuronal death caused by stroke, and NOX4 gene plays a key role in oxidative stress. There is already evidence that NOX4 gene expression is up-regulated in stroke patients.

The “journey” of drug delivery across the blood-brain barrier to the brain has been on the way.

The blood-brain barrier is a barrier between blood and brain tissue. It can prevent certain substances from entering the brain tissue from the blood, such as pathogens, bacteria, etc., but this barrier will also prevent drugs from effectively passing through the barrier and entering the brain. Affect the therapeutic effect of central nervous system diseases.

In recent years, scientists and industry have successively developed a variety of technologies for delivering drugs to the central nervous system, including carrier/receptor-mediated endocytosis, neurotropic viruses, nanoparticles, and exosomes.

Recently, a Canadian biopharmaceutical company Bioasis Technologies (TSXV: BTI; OTCQB: BIOAF, hereinafter referred to as “Bioasis”) announced that it can use its xB3 platform to deliver siRNA to the brain, that is, use peptide-coupled siRNA to penetrate the blood-brain barrier.

After the announcement, Bioasis’ stock price rose 5.41%.

siRNA can trigger RNA interference (RNAi) of gene function, silencing the target gene in a specific sequence. Therapies based on siRNA have been thought to have the potential to solve diseases by targeting specific genes. However, because siRNA itself cannot pass through the blood-brain barrier, gene localization in the brain is considered impossible.

Before announcing that siRNA delivery can be achieved, Bioasis has announced that it has successfully used the xB3 platform to deliver antibodies, enzymes, small molecules, etc., and has proven to be effective in brain and peripheral diseases in brain cancer, neuropathic pain, and lysosomal storage diseases. Efficacy of the environment.

Dr. Wilfred A. Jefferies, a professor at the University of British Columbia, commented on the recent study: “This study demonstrates for the first time that peptides can be transported across the complete blood-brain barrier. This discovery allows this platform to provide a universal method for interventions in brain diseases.”

Cut in from a stroke, looking for the “key” to open the blood-brain barrier

Since its establishment in 2006, Bioasis scientists have been committed to the development of the xB3 platform. They aim to solve the biggest problem currently facing the blood-brain barrier-how to have sufficient drug doses to cross the blood-brain barrier.

Initially, Bioasis called the platform Transcend-peptide. It was discovered based on human transporters. These proteins have very little content in the blood. During the process of crossing the blood-brain barrier, small molecules will attach to the blood-brain barrier. On the surface receptors of endothelial cells, enter the brain through endocytosis, that is, receptor-mediated endocytosis.

Subsequently, Bioasis upgraded the platform, using peptides to assist small molecules and others to cross the blood-brain barrier. After upgrading the platform, peptides are easier to synthesize and are safe at any dose, and the efficiency of delivering drugs into the brain is also improved. They describe the xB3 platform as the “key” to open the blood-brain barrier.

In the research results announced this time, Bioasis evaluated the upgraded platform in the ischemic stroke model.

“Stroke was chosen because it is the most important cause of death in the world and cannot be treated”, the scientists at Bioasis explained in a published paper.

Currently, recombinant tissue plasminogen activator is the only drug approved for the treatment of stroke, but due to contraindications, it can only be used in about 10% of patients. Mainstream methods are turning to pre-treatment to stabilize and reduce brain damage in patients with recurrent strokes or patients at risk of stroke. Therefore, new and effective treatment methods are needed to reduce the frequency and severity of recurrent strokes.

Oxidative stress plays a key role in neuronal death caused by stroke, and NOX4 gene plays a key role in oxidative stress. There is already evidence that NOX4 gene expression is up-regulated in stroke patients.

(Source: company official website)

Scientists at Bioasis use peptides to couple with siRNA. This peptide can promote the transcytosis of siRNA like nanoparticles, help NOX4-targeted siRNA to cross the blood-brain barrier, and achieve the purpose of treating stroke by reducing the expression of NOX4.

Although previous studies have found that free siRNA and siRNA encapsulated by nanoparticles can enter the central nervous system, the premise of these methods is that the blood-brain barrier can only enter after damage to the blood-brain barrier. In this study, the coupling of peptides and siRNA The substance can enter the complete blood-brain barrier, and can accumulate in sufficient quantities to improve the disease.

In order to allow the maximum dose of therapeutic drugs to enter the blood-brain barrier, Bioasis scientists also used the above-mentioned conjugate in combination with traditional fibrinolytic therapy.

As small nucleic acid drugs, siRNA is considered to have set off a new era of small nucleic acid drugs. These drugs have a wide range of indications and can be used for tumors, rare diseases, viral diseases, cardiovascular diseases, inflammatory diseases, etc. However, siRNA drugs themselves preferentially target the kidney and liver, and are easily degraded by nucleases, and siRNA drugs do not cross the blood-brain barrier. Therefore, the target organization of such drugs is limited.

Transport dozens of compounds and build 3 pipelines

Currently, Bioasis has used the xB3 platform to successfully transport dozens of compounds across the blood-brain barrier, including monoclonal antibodies, enzymes, small molecules, siRNA, etc., and its indications cover brain cancer, metabolic and neurodegenerative diseases, including xB3- 001, xB3-002, xB3-007 and other pipelines.

Previously, the company’s CEO, Dr. Deborah Rathjen, revealed in an interview that Bioasis’ pipeline xB3 -001 for breast cancer metastasis to the brain and brain cancer will complete the IND application by the end of 2021.

At the same time, a US consulting company Bluestar BioAdvisors also conducted a commercial evaluation of xB3-001, which may generate annual revenue of 440 million U.S. dollars worldwide. If the drug also works on breast cancer other than the brain, it will generate 3.7 billion U.S. dollars. Annual income.

Bioasis has proven in preclinical experiments that xB3-001 can function outside the brain.

(Source: company official website)

Rathjen also admitted that the advancement of the pipeline is inseparable from the support of funds. After Bioasis was listed on the Toronto Stock Exchange in 2017, it has completed a total of 730,000 US dollars in fundraising in 2019 and 2020. “We will raise funds through non-dilutive financing or other business development methods.”

At the end of 2020, Bioasis and the Italian pharmaceutical company Chiesi Group reached an agreement. Chiesi will use the platform to develop drugs for four lysosomal storage diseases. In return, Bioasis will receive an advance payment of 3 million US dollars, and Milestone payments of up to 138 million U.S. dollars.

In addition, Bioasis has also reached cooperation with more than 20 other research institutions/biopharmaceutical companies.

Figure | Scientific Advisory Committee (Source: Company’s official website)

In addition to financial support, the team is also a core factor supporting Bioasis.

Its chief medical officer, Dr. May Orfali, previously held senior management positions at Pfizer and Wyeth, leading research on sickle cell disease, hemophilia, endocrine and other diseases, and has extensive experience in drug and clinical development; Vice President Mei Mei Dr. Tian has more than 10 years of experience in melanotransferrin related research.

In addition, Bioasis has 3 other medical consultants and 6 scientific consultants, all of whom have extensive experience in the fields of tumors and central nervous system diseases.

(source:internet, reference only)

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