Invented by Cummins; Thomas J., Tamo; Giorgio, Powers; Hannah L., Johnson; Scott Arne, Liu; Shuang, Bristol-Myers Squibb Company

Hemoglobinopathies like sickle cell disease and thalassemia cause much suffering around the world. New research has led to a promising patent application focused on small molecules that could change the way these blood disorders are treated. In this article, we’ll walk through the background, examine the science and past inventions, then break down the details and innovations of this new patent, all in simple words.

Background and Market Context

Let’s start with the basics. Hemoglobin is a special protein in red blood cells that carries oxygen from the lungs to every part of the body. When hemoglobin doesn’t work right, people can get very sick.

There are two major types of hemoglobin in humans. Babies have a type called fetal hemoglobin (HbF). When they are born, their bodies switch to making adult hemoglobin (HbA). HbF holds onto oxygen more tightly than HbA, which helps babies before they are born. After birth, most of the hemoglobin in our blood is the adult form.

Some people have changes in their genes that affect hemoglobin. The two most common hemoglobin diseases are sickle cell disease and beta-thalassemia.

In sickle cell disease, a tiny change in the gene for hemoglobin makes the red blood cells look like sickles or crescent moons. These sickle-shaped cells get stuck in blood vessels and can’t carry oxygen very well. This can cause pain, infections, and other problems. Many people with sickle cell disease do not live as long as people without the disease.

Beta-thalassemia is different. In this disease, the body makes less hemoglobin or makes it in the wrong shape. This means there are fewer healthy red blood cells, and people can feel tired, weak, and get sick easily. Sometimes, people with severe beta-thalassemia need regular blood transfusions to stay healthy.

The market for treating these diseases is huge. Millions of people around the world, especially in Africa, the Middle East, India, and parts of Asia, have sickle cell disease or thalassemia. The cost for treatment is high. Blood transfusions, hospital visits, and medicines add up. Some people even get stem cell transplants, which are risky and expensive.

One drug, hydroxyurea, has been used for many years to help people by making their bodies produce more fetal hemoglobin. But hydroxyurea doesn’t work for everyone and can have serious side effects, like lowering the number of white blood cells and increasing cancer risk. Many families and doctors are searching for safer and better treatments.

Researchers learned that if you can turn “on” the fetal hemoglobin gene in adults, you may be able to help people with these blood diseases. Some new drugs, gene therapies, and even CRISPR “gene editing” approaches are being developed. But gene editing is still very new, expensive, and complicated. Most people still use pills or injections.

Because there is so much need, and because the current treatments do not always work well or are not available to everyone, scientists are racing to find new drugs. The market is very large, and companies that develop new, safer, and more effective treatments could help millions and also do very well financially.

Scientific Rationale and Prior Art

Now, let’s look at the science behind this patent and how it fits with what has already been done.

Hemoglobin is made up of smaller parts called globin chains. Fetal hemoglobin is made of two alpha and two gamma chains. Adult hemoglobin uses two alpha and two beta chains. When beta chains are missing or abnormal, as in sickle cell disease or beta-thalassemia, the red blood cells don’t work right.

One clever idea is to get adult cells to make more fetal hemoglobin again. This can help make up for the broken or missing beta chains. People who naturally keep making some fetal hemoglobin after birth tend to have milder symptoms, even if they have sickle cell or thalassemia.

Scientists have learned that certain proteins in the body act like switches, turning the fetal hemoglobin gene off after birth. Two important “switch” proteins are called ZBTB7A and WIZ. If you can block these proteins, the body may start making fetal hemoglobin again, which could help patients.

Hydroxyurea, as mentioned before, is a drug that can turn on fetal hemoglobin, but it works in a way that’s not fully understood and is not always safe or effective.

Other drugs in the market include L-glutamine, voxelotor, and crizanlizumab. These drugs help sickle cell patients in different ways, such as making red blood cells less sticky or reducing pain, but they do not directly turn on fetal hemoglobin.

Gene therapy is another new approach. Some companies are trying to use CRISPR or other methods to cut out or change the genes for the “off” switches. While this can work, it is very expensive and hard to do. Most patients cannot access this treatment.

Before this patent, some researchers tried to find small molecule drugs that could block ZBTB7A or WIZ or otherwise turn on the fetal hemoglobin gene. Most of these efforts have not led to approved drugs yet. Some patents cover molecules that act in similar ways, but often they are not strong enough, not specific, or have bad side effects.

What is special about the new patent application is that it describes a new family of molecules that are designed to block ZBTB7A and WIZ proteins and induce fetal hemoglobin, with strong activity and less toxicity. The patent lists many different chemical structures, with details about how they are made and tested.

The inventors also show that their compounds work in lab tests. They use special cells that glow when ZBTB7A or WIZ are broken down. The new compounds make these proteins go away and, even more importantly, make the cells start making more fetal hemoglobin.

Compared to older inventions, these molecules have stronger effects in the lab and may have fewer side effects. They are also designed to be taken as pills or given by injection, making them easier for patients. The patent also covers ways to use these molecules with other drugs or treatments, including gene therapy, blood transfusions, or stem cell transplants.

In summary, the scientific rationale is solid. The idea is to block the “off” switch for fetal hemoglobin by targeting ZBTB7A and WIZ, leading to more fetal hemoglobin and better red blood cells. Previous inventions tried similar approaches but did not have as strong or safe molecules as those described in this new patent.

Invention Description and Key Innovations

Let’s walk through the heart of the patent: what’s new, how it works, and why it matters.

The patent covers a group of new chemical compounds. These are small molecules, which means they are not proteins or big gene-editing tools, but rather drug-like chemicals that can be made in a lab and given as pills or injections.

The main “formula” for the molecules is described in detail, with many options for different chemical parts. This means the patent covers a wide range of similar compounds, all designed to work in the same way. The molecules can have small changes—like different atoms or groups attached—which allows scientists to pick the ones that work best and have the least side effects.

The patent also includes special versions of these molecules, called salts, tautomers, isotopologues, and stereoisomers. In simple words, this means the patent covers not just one exact molecule, but many versions that might work better or be easier to make as drugs. For example, some versions might be absorbed better in the body or last longer in the blood.

How do these molecules work? When they enter the body, they find and block the ZBTB7A and WIZ proteins. These proteins normally tell the red blood cell not to make fetal hemoglobin. By blocking these proteins, the molecules let the fetal hemoglobin gene turn back on. This means adults with sickle cell disease or thalassemia can start making more fetal hemoglobin, which helps their red blood cells work better.

The inventors tested these compounds in special cell lines called HUDEP-2 cells. These cells are engineered to glow when ZBTB7A or WIZ are broken down or when fetal hemoglobin is made. The patent shows that their best compounds have strong effects at very low doses, which means they are very powerful.

The inventors also describe how to make these molecules in the lab, using simple chemical reactions. They provide step-by-step recipes for making many examples, with details on how much of each ingredient to use, how to purify the final product, and how to check that the right molecule was made.

Besides making and testing the molecules, the patent also covers how to use them in people. The inventors describe pills, capsules, injections, and other ways to give the drug. They say how much to give, how often, and how to combine the new drugs with other treatments. For example, the new drugs can be used with blood transfusions, gene therapy, or other medicines for sickle cell disease and thalassemia.

A very important part of the patent is the broad protection it claims. It covers not just the exact molecules tested, but also many similar molecules. It covers using these drugs for all types of hemoglobin diseases, including sickle cell, beta-thalassemia, and even anemia. It covers making the drugs as pills, liquids, or injections, and using them with many other therapies.

Another innovation is that the patent includes ways to test which patients might benefit most. For example, people with certain gene types or who do not respond to hydroxyurea could be good candidates for these new drugs. The patent includes ways to measure how much fetal hemoglobin is made in a patient’s blood, to help doctors see if the drug is working.

To sum up, the key innovations in this patent are:

– A new family of small molecule drugs designed to block the ZBTB7A and WIZ proteins, turning on fetal hemoglobin.
– Strong lab data showing these molecules work at low doses.
– Recipes and methods for making many versions of these molecules.
– A wide range of possible uses, including as pills, injections, or in combination with other therapies.
– Broad patent protection for many different chemical versions and medical uses.

If these drugs work well in humans, they could become a new standard for treating sickle cell disease, thalassemia, and other hemoglobin disorders. They could help patients around the world live longer and healthier lives, with fewer side effects and less need for blood transfusions or risky gene therapy.

Conclusion

This patent application represents a big step forward in the fight against hemoglobinopathies. By targeting the “switches” that turn off fetal hemoglobin, the inventors have created a new group of drug candidates that could help millions of people. The science is strong, the need is great, and the patent covers a wide range of molecules and uses. If these drugs make it through testing and into the clinic, they could change the story for patients with sickle cell disease and thalassemia, offering new hope where it is needed most.

For anyone following medical innovation or looking for new solutions in blood disorders, this patent is one to watch closely.

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