NanoGen: One dose to cure type 2 diabetes

8 min readMay 13, 2023

Just imagine that delicious chocolate ice cream on a warm sunny day. The creaminess of the ice cream and perfect crunch of the cone. A few minutes later all that rich goodness is inside your stomach waiting to feed your cells with energy. Now imagine if that sugar leads to painful symptoms or even permanent damage inside your body.

Diabetes is a metabolic disease that results in high blood sugar levels and it can be attributed to exercise, diet, and genetic factors. About 510 million people worldwide have diabetes, and 1.5 million deaths are directly attributed to diabetes each year. The symptoms of diabetes include include fatigue, hunger, increased urination, blurred vision, increased thirst, unexplained weight gain or weight loss, poor wound healing, and foot ulcers.

Around 25% of diabetic patients have a lifetime risk of developing foot ulcers, which are open wounds or sores on the bottom of your feet that make it difficult to walk. Foot ulcers are the leading cause of leg amputations with 14% — 24% of patients requiring a major or minor leg amputation.

Let’s not forget how costly diabetes is. People with diagnosed diabetes incur average medical expenditures of $16,752 per year, which is approximately 2.3 times higher than the expenditures of people without diabetes. Additionally, according to the American Diabetes Association, the total costs of diagnosed diabetes have risen to $327 billion in 2017 from $245 billion in 2012.

Now there are 2 types of diabetics, type 1 diabetics and type 2 diabetics. Approximately 90–95% of Americans who have diabetes have type 2 diabetes. The underlying mechanisms of type 1 diabetes and type 2 diabetes are completely different — type 1 diabetes is characterized by the underproduction of insulin whereas type 2 diabetes is characterized by insulin resistance.

The symptoms of type 2 diabetes include:

fatigue
neuropathy
increased urination
weight loss / weight gain
blurred vision
reduced blood flow to the brain

Reduced blood flow to the brain in patients with type 2

Type 2 diabetes is a chronic condition that impacts every aspect of a person’s life, from their diet and exercise routine to their social and emotional well-being. Type 2 diabetics suffer from insulin resistance where cells are unresponsive to increasing amounts of insulin, which leads to high blood sugar. People with type 2 diabetes also have an increased risk for developing heart disease, stroke, eye, and kidney disease.

Mechanisms of Type 2 Diabetes

Insulin is a hormone produced by the pancreas to regulate the amount of glucose in our blood. In healthy individuals, insulin causes glucose to move inside the cells, thereby reducing the amount of glucose in our blood. In type 2 diabetics, unresponsiveness to insulin, causes more glucose to be produced, leading to high blood sugar.

But what exactly causes more glucose to be produced? To understand this, we need to understand the metabolic pathway that is kicked off when insulin enters cells.

When insulin latches onto insulin receptors in fat (adipocytes) and muscle cells, it stimulates a transport protein called GLUT 4 to bring glucose inside the cell. GLUT 4 is essential for maintaining normal blood sugar levels in our body. The deletion of GLUT 4 from muscle or adipocytes promotes insulin resistance to a much greater extent than the deletion of insulin signaling components.

It also induces the a process called lipolysis, which breakdowns fats and other lipids into fatty acids. These fatty acids in turn are broken down further in the liver into triglycerides through a process called de-novo lipolysis. These triglycerides are stored in adipose tissue and serve as a source of energy for the body.

Insulin Resistance

The biggest effect of insulin resistance is decreased glucose transport. In adipocytes and muscle cells, unresponsiveness to insulin leads to decreased GLUT 4 activity. Downregulation of GLUT 4 is responsible for impaired glucose uptake, a major characteristic of type 2 diabetes.

Insulin resistance disrupts also disrupts processes in the liver. It can lead to a decrease in glycogenolysis, the breakdown of glucose into glucose-1-phosphate and glucose, and gluconeogenesis, the formation of glucose from noncarbohydrates, both of which increase ATP in our bodies (makes sense why fatigue is a symptom of type 2 diabetes). Additionally, insulin resistance also leads to increased de-novo lipogenesis, which results in high levels of triglycerides. High levels of triglycerides can to increased risk of heart attacks, strokes, and pancreatitis.

So insulin resistance plays a big role in type 2 diabetes and its symptoms. But insulin resistance is also responsible for many other diseases, including cardiovascular disease, polycystic ovarian syndrome, metabolic syndrome, and nonalcoholic fatty liver disease.

At NanoGen, we are upregulating GLUT 4 using a gene therapy approach to reverse insulin resistance and cure type 2 diabetes. Cool, right? Except, how does our solution actually work?

The Solution

CRISPR

You’ve probably heard about CRISPR. Clustered Regularly Interspaced Palindromic Repeats. CRISPR is a defense mechanism in bacteria against viruses that utilizes molecular scissors to cut out viral genome. We have adapted this to our benefit using the CRISPR — Cas 9 system, which can edit the human genome!

The CRISPR — Cas 9 system is already being used to treat cancer, cystic fibrosis, and and Huntington’s disease. It has already been used to treat HPV and correct mutations responsible for muscular dystrophy in mice.

A regular CRISPR — Cas 9 system cuts out certain base pairs of DNA and replaces it with a new sequence. To upregulate GLUT 4, we don’t want to modify the base pairs, but instead activate the gene that is responsible for producing GLUT 4. The production of GLUT 4 is meditated by the gene, SLC2A4, if we upregulate SLC2A4, we upregulate GLUT 4. But how do we upregulate SLC2A4?

We can use something called a CRISPR Activator, which is a little different from the CRISPR Cas 9 system. Instead of modifying base pairs, a CRISPR Activator targets the promoter of a gene to activate it. The promoter of a gene is just a region of DNA where proteins can bind to initiate the transcription of that gene, which in our case is SLC2A4. When a gene is activated, it directs the production of the proteins that the gene codes for, (i.e. GLUT 4 in the case of SLC2A4).

Nanoparticles

Now we can’t just inject someone with a CRISPR Activator. We have to specifically deliver our gene therapy solution to adipocytes. To do this, we can use nanoparticles as targeted delivery systems. There are many different types of nanoparticles we can use including metal nanoparticles, polymer nanoparticles, lipid nanoparticles, carbon nanoparticles, ceramic nanoparticles, and magnetic nanoparticles.

In fact, the COVID 19 vaccine involved the use of lipid nanoparticles to encapsulate mRNA and antigens that would elicit an immune response to the COVID 19 infection. However, the problem with lipid nanoparticles is that they can spill out the stuff inside of them under temperature and pressure changes.

To combat this problem, we are using metal nanoparticles. The advantage of metal nanoparticles, specifically metal organic frameworks (MOF) is that are extremely stable and even degrade effectively in the body after after delivering the intended drug or therapeutic agent. You might say, metals in the body?!?! Well, recently the FDA approved Cu (copper) metal ions for nanoparticles. Certain amounts of metals in the body is actually good for us. For example, bodily tissue contains various metals, such as copper (68 μM), manganese (180 μM), nickel (2 μM), and zinc (180 μM).

At NanoGen we are specifically using copper metal ions and tetraphosphate acid linkers to manufacture our nanoparticles.

Some other unique advantages of MOFs include large surface areas, high stability in high temperatures and chemical environments, and high programmability, which makes it easier to engineer MOFs to target specific cells.

But how do MOFs travel through the bloodstream and reach their destination? Because nanoparticles are so small, they can pass through the pores of the blood vessels and enter the bloodstream. Then, via a process called active targeting, we are able to modify the surface of the nanoparticles with specific ligands such that they can bind to receptors or biomolecules overexpressed on the surface of the target cells.

To deliver our solution to adipocytes, we would have to attach a specific type of ligand to the surface of the MOFs— one that can be recognized by the cell’s receptors and result in the uptake of the nanoparticles. The ligands function almost like a Trojan horse, allowing the nanoparticles to enter the cell in disguise.

White adipose tissue (WAT) have 2 important types of receptors called AdipoR1, AdipoR2. The activity of these receptors is regulated by Adiponectin, a protein hormone produced by adipocytes. We can specifically use Adiponectin as our targeted ligand that can bind to AdipoR1 and AdipoR2 and induce the uptake of the MOF nanoparticles in the cell. Additionally, since white adipose tissue accounts for 3% — 70% of humans’ total body mass, by using Adiponectin we are virtually targeting all adipocytes in the body.

Our Approach

At NanoGen, we are using nanoparticles, specifically MOF 16, to deliver a gene therapy approach via the bloodstream. Our solution works by targeting the SLC2A4 gene and upregulating GLUT — 4 using a CRISPR activator. By upregulating GLUT 4, we aim to increase the uptake of glucose into cells and reverse insulin resistance. We are a moonshot company delivering one dose to cure type 2 diabetes, and we hope you will join us on this mission.

Learn more about our mission on our website: https://nanogenx.webflow.io/