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Innovative Medicine from Israel

In the month of May just past, there were a number of exciting new developments in the area of pharmaceutical research announced or released by the Israeli “Start-up Nation” medical research community.

Cancer therapies

One of these was the release by Genprex, Inc. a company focused on developing life-changing therapies for patients with cancer and diabetes through clinical-stage gene therapy. 

Genprex’s technologies are designed to administer disease-fighting genes to provide new therapies for large patient populations with cancer and diabetes who currently have limited treatment options. 

In the field of oncology, Genprex has now dosed the first subjects in Phase I/II clinical trial of its drug candidate Reqorsa Immunogene Therapy (quaratusugene ozeplasmid) along with Tagrisso (osimertinib, from AstraZeneca) to treat late-stage non-small cell lung cancer (NSCLC).

Reqorsa leverages Gentex’s ONCOPREX Nanoparticle Delivery System. It comprises the TUSC2 gene that encodes tumor suppressor candidate 2 proteins. The gene is encapsulated in a nanoparticle developed from lipid molecules. It possesses a net positive electrical charge and so can precisely act on target cancer cells that usually have a negative electrical charge. 

Gentex believes ONCOPREX is the first systemic gene therapy delivery platform used for cancer in humans. It is administered intravenously, where it is then taken up by tumor cells that are deficient in expressing tumor suppressor candidate 2 proteins. Reqorsa has been shown to interrupt cell signaling pathways that permit the replication and proliferation of cancer cells. It has a multimodal mechanism of action that can also re-establish pathways for apoptosis (programmed cell death) and modulate the immune response against cancer cells. Reqorsa has also been shown to block mechanisms that create drug resistance.

Coming soon – new developments in anti-depressant treatment.

According to the WHO, depression afflicts nearly 300 million people worldwide. About three-quarters of a million people commit suicide every year. However, even after decades of research and billions of dollars, there still remains much to be learned about the biological mechanisms underlying depression and finding ways to ameliorate those mechanisms with drugs. Most significantly, there have been no major breakthroughs in the treatment of depression since 1987, which saw the approval of Prozac. Other existing antidepressant drugs fail to relieve symptoms in about one third of depressed patients and even when they do work, there can be long delays, which can prove fatal in subjects with suicidal tendencies.

Now, an Israeli study has revealed that the mechanism of ketamine’s action on potassium channels in neurons may lead to improved therapies for depression.

Ketamine is an anesthetic that was best known in the past when used in smaller doses as a party drug. But in 2017, it was greeted as a “new hope for depression”, even hitting the front pages in a Time magazine cover story. In 2019, Janssen, a European subsidiary of US pharma giant Johnson & Johnson, released the first ketamine-based antidepressant, a nasal spray based on esketamine.

Until now, due to US FDA limits imposed because of the lack of clarity on how ketamine works, the spray has been prescribed mainly for depressed patients who have not been helped by other therapies. 

Now, a new study conducted at the Weizmann Institute of Science in Rehovot and at the Max Planck Institute of Psychiatry in collaboration with the Helmholtz Zentrum in Munich is showing how ketamine works. The results, published in Neuron magazine, reveal new details of the mechanism of ketamine working. It can pave the way toward the promotion of ketamine as a safe and effective treatment for depression. 

They established the molecular cascade that is triggered by ketamine, leading to its sustained antidepressant effects, according to the lead scientist, Dr. Juan Pablo Lopez said. It focused on one brain region (the ventral hippocampus) that had been thought to be associated with the antidepressant effects of ketamine. In the study, by mapping out the brain activity of mice that were administered ketamine, researchers were able to focus on a specific gene (Kcnq2), which plays a central role in enabling the passage of potassium ions through neural junctions, which crucial for maintaining the activity and stability of neurons. By enhancing the levels of activity in Kcnq2 potassium channels by administering another drug that is known to be also using potassium channels (retigabine – used as an anti-epilepsy medication), the study found strongly increased activity with the drug. 

This led the researchers to the major finding, that ketamine exerts its lasting antidepressant effect by enhancing the Kcnq2 potassium channels in a certain subtype of glutamate-sensitive neurons. According to Dr. Lopez, “…ketamine produced the same benefits when given in smaller doses than usual, which may help reduce its unwanted side effects.”

There is a good reason for the excitement over ketamine-based therapies. It produces a response within hours and the antidepressant action can last for days afterwards, even persisting after all traces of the drug itself have cleared. The conclusion is that it’s the body’s response to ketamine rather than ketamine itself that produces the desired effect. Until now the nature of this response has been unclear, but thanks to the new study, this has been explained by identifying the molecular cascade that is triggered by ketamine, leading to its sustained antidepressant effects, as Dr. Lopez said.

Ketamine produced the same benefits when given in smaller doses than usual, which may help reduce its unwanted side effects. Importantly, since both ketamine and retigabine already have FDA approval, testing their combined action in humans can proceed immediately.

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