Healix: Curing Diabetes with Gene Editing

Meet Healix, a gene therapy company that envisions a world free from the burden of type 2 diabetes. By harnessing the power of CRISPR technology we’re going to revolutionize gut health and metabolic balance to create a future where patients have a one-time cure for the disease.

Healix, company harnessing the power of gene editing to treat and cure type 2 diabetes.

We are committed to:

• Pioneering the development of a safe and effective CRISPR-based therapy that targets the gut bacteria responsible for producing the metabolite causing impaired insulin signaling in patients with type 2 diabetes.
• Conducting rigorous research and clinical trials to ensure the efficacy and safety of our approach.
• Fostering collaboration with the scientific community and patient advocacy groups to accelerate progress towards a cure for type 2 diabetes.
• Advancing the understanding of the gut microbiome’s role in metabolic health and developing personalized therapeutic solutions for type 2 diabetes and related conditions.

By achieving our mission, we aim to:

• Improve the quality of life of type 2 diabetes patients.
• Reduce the healthcare burden associated with this chronic disease.
• Pave the way for future microbiome-based therapies to address other health challenges.

Millions of People are Impacted by Diabetes

In 2021, approximately 540 million adults (20–79 years) were living with diabetes. That means that 10.5% of the adult population is suffering with a disease that occurs when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces.

90% to 95% of people with diabetes have type 2 diabetes. These patients are living with symptoms such as slow healing wounds, recurrent infections in the skin, blurred vision, tingling or numbness in hands and feet, lack of energy, tiredness, frequent urination and excessive thirst and dry mouth.

Type 2 diabetes affects how your body uses sugar (glucose) for energy. It stops the body from using insulin properly, which can lead to high levels of blood sugar if not treated. Over time it can cause serious damage to the body, especially blood vessels in the heart, eyes, kidneys and nerves.

In 2019, diabetes was the direct cause of 1.5 million deaths and 48% of all deaths due to diabetes occurred before the age of 70. Diabetes is also a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. People with diabetes develop problems with their feet from nerve damage and poor blood flow. This can cause foot ulcers and may lead to amputation. In 2019, diabetes and kidney disease due to diabetes caused an estimated 2 million deaths. Raised blood glucose causes around 20% of cardiovascular deaths [1].

Current Diabetes Treatments are Insufficient and Ineffective

There are many diabetes treatment options which are not able to fulfill the burden caused by the disease. People with type 2 diabetes need to take medicines to help manage their blood glucose levels. These can include injections or other medicines, such as metformin, sulfonylureas, and sodium-glucose co-transporters type 2 (SGLT-2) inhibitors.

Patients need to take medicines to lower their blood pressure and strains to reduce the risk of complications, and additional medical care may be needed to treat the effects of diabetes, such as foot care to treat ulcers, screening and treatment for kidney disease and eye exams to screen for retinopathy (which causes blindness).

1. Insulin injections

Insulin injections have long been a cornerstone of diabetes treatment, providing a direct way to control blood glucose levels by replacing the insulin that the body either cannot produce or cannot use effectively. However, insulin therapy has its limitations and challenges. One of the main drawbacks of insulin injections is the risk of hypoglycemia, particularly in patients with poor glycemic control or those who do not adhere to their treatment regimen. This can result in severe adverse events, including coma or death. Additionally, hypoglycemia can lead to rebound hyperglycemia, making blood glucose control even more challenging.

Insulin therapy also requires frequent monitoring of blood glucose levels, multiple daily injections, and constant adjustment of insulin doses, which can be cumbersome for patients. This complexity may result in poor treatment adherence and suboptimal glycemic control. Furthermore, the use of insulin therapy is associated with weight gain, which can amplify insulin resistance and worsen diabetes management. This loop effect is a significant concern, especially for patients already struggling with obesity or metabolic syndrome. Considering these limitations, there is a clear need for alternative treatment options that offer better glycemic control, reduce the risk of hypoglycemia, and improve the quality of life for patients with diabetes.[1][2]

Insulin injection

2. Metformin

Metformin is a medicine that reduces insulin resistance and allows the body to use its insulin more effectively. It is regarded as the first-line treatment for type 2 diabetes in most guidelines worldwide. Despite its widespread use, metformin has several drawbacks. Its gastrointestinal side effects, including nausea, vomiting, and diarrhea, affect up to 30% of users. Additionally, metformin is not suitable for patients with renal impairment or those at risk of lactic acidosis. The drug’s efficacy varies among patients, sometimes requiring additional medications to manage blood glucose levels effectively. Lastly, long-term metformin use may lead to vitamin B12 deficiency. Considering these limitations, healthcare providers should personalize treatment plans, weighing the pros and cons for each patient.[1][2]

3. Sulfonylureas

Sulfonylureas are a class of oral medications commonly used to treat type 2 diabetes by stimulating insulin release from the pancreas, thereby reducing blood glucose levels. While sulfonylureas have been a mainstay in diabetes treatment, they have several limitations, making them suboptimal in certain situations. Firstly, sulfonylureas rely on the presence of functioning beta cells in the pancreas, rendering them ineffective for patients with type 1 diabetes. Furthermore, their action can lead to hypoglycemia, particularly in elderly patients and those with renal impairment. This risk of hypoglycemia can be severe and poses a significant challenge in managing blood glucose levels safely. Additionally, sulfonylureas may not be sufficient for achieving glycemic control in some patients, necessitating the addition of other medications. This can increase the complexity of treatment regimens and potentially lead to drug interactions.

“As a diagnosed Type 2 Diabetes patient taking daily insulin injections, I can confirm that this treatment is tiring and really, substandard. I am extremely excited for new technologies to come up with new ways to combat T2D.” — Yash Bhandari. The patient also reported hating to take insulin injections, and although the pills were better, they didn’t work for later/more serious stages.

The Economic Burden of Diagnosed Diabetes

• Staggering Cost: The total cost of diagnosed diabetes in the US for 2022 was estimated at a whopping $412.9 billion. This translates to one out of every four healthcare dollars spent on caring for people with diabetes.
• Breakdown of Costs: Direct medical costs account for $306.6 billion, with the remaining $106.3 billion being indirect costs due to lost productivity (reduced employments due to disability accounted for a $28.3 billion loss, and presenteeism, a $35.8 billion loss) and premature deaths ($32.4 billion). Glucose-lowering medications and diabetes supplies account for 17% of the total direct medical costs attributable to diabetes.
• Per Person Impact: People with diabetes incur significantly higher medical expenses, averaging $19,736 annually, with $12,022 directly attributable to the disease. This is 2.6 times higher than what would be expected without diabetes.
• Rising Costs: Direct medical costs have inflated by 7% since 2017 and 35% since 2012 (adjusted for inflation).
• Prevalence and Spending: The absolute number of people with the disease has grown. This translates to increased healthcare spending, particularly on hospital stays and medications.
• Societal Burden: The immense cost of diabetes burdens not just the healthcare system but also society as a whole, due to lost productivity and premature deaths. [1]

How Healix is Making a Cure for Type 2 Diabetes

Fecal transplants (transferring gut bacteria from healthy people to those with diabetes) have shown that gut bacteria can directly influence how sensitive the body is to insulin.

One specific metabolite that has been studied is imidazole propionate (ImP). It was found that type 2 diabetics have higher levels of ImP, which reduces their ability to regulate their glucose levels.

That is because diabetic patients have higher levels of imidazole propionate (ImP) producing bacteria when compared to healthy patients, and they lack the type of bacteria that is negatively correlated with the production of this metabolite. The production of ImP is catalyzed by the bacterial enzyme, urocanate reductase. Our therapy is going to target ImP production and restore normal metabolic functions. [1]

Imp messes with how insulin works. Imagine insulin is a key that unlocks your cells to let sugar (glucose) in for energy. Imp throws a wrench in the lock, making it harder for the key (insulin) to work. Insulin needs a helper protein called IRS (Insulin Receptor Substrate) to unlock the cells. Imp lowers the levels of this helper protein. With fewer helpers (IRS), insulin has a harder time unlocking the cells, leading to sugar buildup in the blood. This sugar buildup can contribute to type 2 diabetes.

Our gene therapy targets the metabolic pathway that produces ImP. By using CRISPR technology to edit the urdA gene in the genome of these bacteria we can reduce the production of this metabolite and avoid impaired insulin signaling.

This product is going to be injected intravenously through IV and can be easily administered by pharmacy, hospital and/ or clinic. Differently from other diabetes patients, what is offered by Healix is a one-time treatment for type 2 diabetes.

IV therapy

Our Vision for the Future

Unlike traditional treatment options, such as metformin, sulfonylureas, or insulin injections, this targeted therapy aims to minimize the risk of type 2 diabetes development and progression without the need for daily medications or the risk of hypoglycemia. By offering a more tailored and effective solution, Healix’s treatment has the potential to not only significantly improve glycemic control but also reduce the long-term health complications associated with diabetes, ultimately enhancing the quality of life for millions of individuals.

How the Technology Works

CRISPR-Cas9 (CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats) is a technology which can locate, cut, paste, and edit genes. Here’s how we’re using it:

There are two main components to the CRISPR-Cas9 technology, the guide RNA, and the Cas9 enzyme.

The guide RNA acts as a molecular GPS system, which, when inserted into the body, locates the specific gene sequence we are attempting to target, the urdA gene.

The guide RNA is a strand of RNA, made of nucleotides, which are the same chemical units that DNA is made up of. This RNA is designed to match the specific nucleotide sequence of the target gene.

Our CRISPR-based treatment is going to consist of an injection containing both a messenger RNA encoding a DNA-cutting enzyme (white) and another RNA (blue) that guides it to a specific gene sequence (green).

The Cas9 enzyme is attached to the guide RNA, and acts as a pair of molecular scissors. It’s going to cut the gene that codes for urocanate reductase’s function of reducing urocanate to ImP.

Once both of these components are developed and attached to each other, they are ready for delivery. In order to do so, we’re going to use the plasmid DNA method. Plasmid DNA is a small, circular package containing the CRISPR-Cas9 compound.

Once the CRISPR-Cas9 compound has been introduced to the cells, it is time for the guide RNA to locate the target gene, and guide the Cas9 enzyme to the correct location. The Cas9 then makes a double-strand break in the DNA. Both sides of the DNA are cut at that location, creating two separate pieces. When this cut is made, the cell’s natural DNA repair mechanism is triggered, and the DNA will rejoin the broken ends without the original sequence that was cut.

Click here to learn more about what ImP is, how it is produced, and how it leads to impaired insulin signaling.

A Final Comparison: Patient Outcomes With & Without Our Therapy

Without our CRISPR-based therapy:

• Prevalence: The number of people with type 2 diabetes is going to increase, leading to rising healthcare costs, particular for medication and hospital stays. By 2045, the International Diabetes Federation projections show that 1 in 8 adults, approximately 783 million, will be living with diabetes, an increase of 46%. [1]
• Cost Burden: The economic burden of diabetes on individuals and the healthcare system would continue to rise as the number of cases increases.
• Symptoms: People with type 2 diabetes would continue to experience the same symptoms, such as slow healing wounds, recurrent infections, and vision problems.
• Complications: Diabetes can lead to serious complications like heart disease, stroke, and kidney failure. Without a one-time cure, these complications would still occur and likely its prevalence would increase, as occurrence of diabetes also increases. Comorbidities ranging from hypertension and obesity to liver disease and sleep apnea are common with type 2 diabetes: A recent study of more than 1.3 million people showed that nearly 98% of adults with type 2 diabetes have at least one comorbid chronic disease and almost 90% have at least two. [1][2]
• Current Treatments: People with type 2 diabetes would still rely on existing treatment options such as metformin, sulfonylureas, and insulin injections. Each has limitations, like side effects, hypoglycemia risk, and the need for ongoing monitoring and adjustments.
• Quality of life: Constantly managing blood sugar, taking medications, and dealing with potential side effects can significantly impact a person’s quality of life. Without a one-time solution, this burden would persist.
• Mortality Rates: Diabetes remains a leading cause of death globally. Without a way to address the root cause, mortality rates would likely increase. In 2019, diabetes was among the top 10 leading causes of death globally. 7 of the 10 causes were noncommunicable disease, and among them, diabetes. All noncommunicable diseases together accounted for 74% of deaths globally in 2019. [1]

With our CRISPR-based therapy:

• CRISPR offers the potential for a one-time gene editing approach that could target the root cause of the disease in specific gut bacteria, potentially leading to a permanent solution and significant cost savings.
• This one-time approach could significantly reduce long-term healthcare needs associated with managing the disease.

Roadmap to Rollout

Healix is looking to expand our team to take our gene therapy to the next level. We plan the next few years to look like this:

1. Pre-clinical Trials:

• Develop and test safe and effective delivery methods for CRISPR-Cas9 to target gut bacteria.
• Refine the CRISPR guide RNA to ensure specific targeting of the urdA gene without unintended effects.
• Conduct in vitro and in vivo studies to assess the efficacy and safety of the therapy in reducing ImP production and improving insulin signaling in animal models of type 2 diabetes.

2. Clinical Trials:

• Phase 1: Evaluate the safety and tolerability of the therapy in healthy volunteers.
• Phase 2: Assess the efficacy of the therapy in reducing ImP levels and improving glycemic control in patients with type 2 diabetes.
• Phase 3: Large-scale clinical trials to confirm efficacy and safety compared to standard diabetes treatments.

3. Regulatory Approval:

• Seek regulatory approval from relevant bodies (e.g., FDA) based on clinical trial data.

4. Manufacturing and Distribution:

• Develop a scalable and cost-effective manufacturing process for the CRISPR-Cas9 therapy.
• Establish distribution channels to ensure access to the therapy for patients.

Technical Gaps to Address:

• Delivery Method: Current methods for delivering CRISPR-Cas9 to gut bacteria efficiently and safely need improvement.
• Off-Target Effects: Mitigating the risk of the CRISPR system editing unintended genes in the gut microbiome needs further research.
• Long-Term Effects: The long-term effects of manipulating gut bacteria with CRISPR need to be thoroughly investigated.
• Durability: Understanding how long the edited gut bacteria persist and their impact on ImP production over time is crucial.
• Specificity: Ensuring the CRISPR system targets only the desired bacterial strains producing ImP needs further refinement.

These are the things we need to figure out. By overcoming these hurdles with the aid of other technologies, we’re going to create a safe and effective CRISPR-based therapy to cure type 2 diabetes.

The Future We’re Driving Towards

By targeting the genome of ImP producing bacteria we’re going to enhance insulin signaling in type 2 diabetes patients. By doing so, elevated blood sugar levels due to the cells’ inability to take in glucose effectively are going to be avoided.

By addressing the problem at its source, a CRISPR-based therapy could revolutionize type 2 diabetes treatment, offering both healthcare cost reduction and improved patient outcomes.

As the search for more effective diabetes treatments continues, our groundbreaking CRISPR-Cas9-based therapy offers a beacon of hope for those affected by this debilitating disease. By harnessing the power of gene editing to target the underlying cause of type 2 diabetes, we move one step closer to a world where living with diabetes is no longer defined by daily struggles and limitations.

Healix, founded by Giovana Ferreira, Lukas Winter, Mansi Bhandari and Nairi Shepherd, represents hope, not just for those suffering from type 2 diabetes, but also for healthcare systems burdened by its costs. With unwavering dedication and cutting-edge science, Healix is paving the way for a future free from the shadow of type 2 diabetes.

Contact Info

Website

Founders:
Giovana Ferreira — LinkedIn, Substack

Lukas Winter — LinkedIn, Medium, Substack

Mansi Bhandari — LinkedIn, Medium, Substack

Nairi Shepherd — LinkedIn, Medium, Substack

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