Project Description

Assessing the impact

It is commonly associated with a diverse set of symptoms that can range from physical to metabolic and even psychological ones.

The physical symptoms include a significant increase in the patient’s body weight and the accumulation of excess adipose tissue. The sufferers are likely to experience shortness of breath and chronic fatigue due to alarmingly low energy levels. Moreover, obesity can cause joint and back pain attributable to the increased mechanical stress, while severe hyperhidrosis and even skin problems are considered quite common among patients¹.

From a metabolic and hormonal perspective, individuals with obesity often face significant endocrine imbalances. In men, this may include reduced testosterone levels, while in women, menstrual irregularities and infertility are common. In some cases, women may also develop Polycystic Ovary Syndrome (PCOS), a condition strongly associated with obesity-related insulin resistance and hormonal imbalance^2,3.

As a chronic disease, obesity can be commonly associated with a wide range of health complications such as various cardiometabolic disorders. For instance, it has been found that individuals suffering from obesity are susceptible to Type 2 Diabetes -Diabesity-, Hypertension, Dyslipidemia and increased risk of cardiovascular disease. A number of respiratory issues are also commonly attributed to obesity with Asthma and Obstructive Sleep Apnea growing in prevalence. Moreover, it is quite crucial that we mention the gastrointestinal and liver complications that patients may have to deal with. Such complications usually include Non-Alcoholic Fatty Liver Disease and Gastroesophageal Reflux Disease. Last but definitely not least, it has been found that obesity is linked to a subsequently higher risk of several types of cancer¹.

Obesity is also known to severely affect the patient's mental health as it takes a serious toll on their self-esteem. Individuals are likely to suffer from mental disorders such as depression and anxiety, that can trigger emotional or binge eating episodes, while also having to battle the heavy social stigma that often comes with obesity¹.

Limitations of current strategies

Pharmacological treatments: Effectiveness and drawbacks

The currently available drugs for obesity fall into two categories: FDA-approved weight-loss medications and emerging therapeutic agents. The first category includes GLP-1 receptor agonists, monoamine modulators and lipase inhibitors that mainly suppress appetite or reduce calorie absorption^4,5.

While these drugs offer measurable weight loss, they do not address the underlying causes of obesity and often require continuous administration, potentially leading to adverse side effects. Among the most commonly reported are gastrointestinal symptoms, including nausea, vomiting and abdominal pain. Although less frequent, more serious complications such as pancreatitis, gastroparesis and kidney disease, have also been documented^4,5.

The two primary limitations of current pharmacological treatments are, first, the significant weight regain observed following discontinuation and second, the disproportionate loss of lean body mass relative to adipose tissue^4,5. Moreover, most of these drugs were originally approved for diabetes rather than weight loss and their off-label use poses health risks for non-diabetic individuals, while also causing shortages for diabetic patients^4,5.

Experimental therapies and surgical interventions

Emerging therapeutic agents, such as drugs targeting energy expenditure, adipose tissue browning, or gut microbiota, aim to tackle obesity more holistically, but remain largely experimental and unapproved⁴.

Although bariatric surgery can lead to substantial weight loss, it is far from an ideal or widely applicable solution. It is invasive, carries non-negligible perioperative and long-term risks and entails high costs. Additionally, a proportion of patients experience clinically significant weight regain as more time passes after surgery⁶.

Our approach: A targeted and lasting solution

In contrast, our therapeutic approach introduces a novel and potentially long-lasting solution for obesity, with minimal side effects. Our strategy directly tackles the root neuroendocrine dysfunction underlying the disease, rather than merely suppressing appetite or altering nutrient absorption.

From vision to action: The Morphe Project

Obesity is frequently framed as a matter of personal willpower or appearance, an oversimplification that fuels stigma and obstructs effective care. Rather than managing symptoms, we chose to focus on the biological roots of this complex condition, leveraging the potential of synthetic biology to explore more effective and lasting solutions.

Our project began with a simple yet powerful question:

What if the body could be guided to heal itself?

"Morphe" is more than a scientific initiative, it is a call to reshape how we perceive obesity, health and human transformation.

The name Morphe, drawn from the Ancient Greek "μορφή" (form, shape), reflects not only the physical structure of the body, but also the fluid nature of identity and our capacity for change. Inspired by Morpheus, the god of dreams who gave shape to the intangible, our project seeks to give form to possibility: a future in which obesity is addressed not through force or stigma, but through biological understanding, technological precision and human compassion.

Morphe is a reminder that science can heal not only the body, but also the way we understand ourselves and each other.

In a few words...

Morphe employs a genetically engineered circuit that has been rationally designed to facilitate targeted and adaptive gene therapy for obesity at the cellular level. The system integrates environmental sensing, logical computation and autonomous therapeutic regulation within a single genetic circuit. The therapeutic core consists of an shRNA embedded within a microRNA scaffold, designed to mimic endogenous microRNA structure and thereby evade immune detection. This molecular Trojan horse selectively silences the HDAC6 mRNA in the hypothalamus. HDAC6 protein is upregulated in obese patients, disrupting insulin’s and leptin’s metabolic pathways in the hypothalamus.

Rather than acting broadly, this shRNA therapeutic molecule is conditionally expressed: restricted to AgRP neurons and activated only in the presence of leptin or/and insulin resistance. This allows for targeted intervention specifically during metabolic dysfunction, while remaining inactive during normal physiological states.

Therapeutic activation is governed by a multi-layered logic system that restricts expression to disease-relevant neurons and conditions. To ensure safety during normal physiological states such as fasting, a fail-safe mechanism leveraging the endogenous miR-7-5p suppresses circuit activity. Delivered via lentiviral vectors through intranasal administration for permanent genomic integration, this living therapeutic system continuously monitors metabolic signals and dynamically modulates its response, remaining transcriptionally silent under homeostasis and reactivating upon dysfunction.

By embedding programmable logic directly into the brain’s regulatory circuits, Morphe delivers a one-time treatment capable of long-term, adaptive regulation-opening a new chapter in the design of intelligent gene therapies for complex metabolic diseases.

Morphe demonstrates how synthetic biology can create the next generation of precision therapeutic products that don't just treat disease, but intelligently prevent its recurrence.

Precision at the core

At the heart of our therapeutic system lies miRE, a microRNA-mimicking shRNA, designed to silence HDAC6 , a key contributor to metabolic dysregulation in obesity.

Unlike traditional shRNA approaches that can trigger innate immune responses and off-target effects, miRE uses a natural miRNA scaffold to camouflage itself within the cell. This biomimetic disguise enables it to seamlessly integrate into the cell's native RNA interference machinery, enhancing biocompatibility and reducing immunogenicity⁷.

By hijacking endogenous miRNA processing pathways, miRE delivers sustained and targeted silencing of HDAC6⁸. This makes miRE the ideal therapeutic payload for a conditional gene silencing strategy: potent, stealthy and ready to act only in the right cellular context.

Dual sensing circuit logic

To ensure precise control over where and when HDAC6 is silenced, we engineered a three-tiered genetic logic system combining transcriptional and post-transcriptional regulation.

Logic layer 1: Transcriptional AND Gate⁹

Our system employs a split transcription factor design, using the classic GAL4-VP16 architecture¹⁰:

• The AgRP promoter drives Gal4 expression, ensuring neuron-specificity.
• The synthetic FoxO1-responsive promoter drives VP16 expression, activated only in states of metabolic dysfunction (leptin/insulin resistance).

The expression of the miRE cassette is only observed when both inputs are present.

Logic Layer 2: Post-transcriptional failsafe

According to bibliography FoxO1 is also expressed during fasting¹¹, a normal physiological condition. To prevent inappropriate activation during fasting, we added a failsafe layer using the endogenous fasting-associated microRNA miR-7-5p¹².

• We engineered miR-7-5p binding sites into the 3' UTR of the miRE transcript.
• During fasting, elevated levels of miR-7-5p bind to the engineered target sites positioned downstream of the miRE mRNA¹³. This interaction promotes targeted degradation of the transcript, effectively silencing the circuit at the post-transcriptional level and ensuring precise control in response to metabolic state.

Circuit summary

This dual-input and failsafe logic results in a therapeutic system that activates only in the pathological state and stays silent during healthy conditions.

Delivery approach

To achieve long-term functionality and self-regulation, we deliver our full gene circuit using a third-generation lentiviral vector, a clinically validated tool used in FDA-approved gene therapies¹⁴.

Once integrated into the host genome, the circuit becomes a metabolic watchdog activating only in the presence of leptin or insulin resistance and remaining dormant in healthy states. If dysfunction returns, the circuit reactivates autonomously, without the need for further intervention.