Our Science | Muna Therapeutics

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Inspired by Patients “To Remember”

Age is the most significant risk factor for developing neurodegenerative diseases that affect key brain functions like cognition. As the global population ages, the prevalence of neurodegenerative diseases is growing. Disorders like Alzheimer’s, Parkinson’s and Multiple Sclerosis result in disability and death of millions of patients around the globe and incur nearly $1.5T annually in health care costs in the EU and US alone.

Muna colleagues work tirelessly to discover and develop disease modifying small molecule therapies for disorders that impact memory, movement, language, behavior, and personality. We transform groundbreaking science into life-changing therapies that preserve cognition and other brain functions and enhance resilience to neurodegeneration. Our name reflects our focus on preserving key brain functions, like cognition, so patients can live their best lives: Muna means “to remember” in Old Norse.

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Leveraging Resilience to Benefit Patients

Alzheimer’s, Parkinson’s and Multiple Sclerosis, among other neurodegenerative diseases, share features of neuroinflammation, cellular dysfunction, and neuronal cell loss. Our scientific focus includes studying brain resilience to discover and develop new medicines that can slow or stop the progression of these processes and preserve brain functions like cognition.

Resilience is the brain’s ability to protect core functions, like cognition, despite the presence of misfolded protein pathology that is a hallmark of many neurodegenerative diseases. About a third of non-demented elderly individuals have substantial misfolded protein pathology in the brain, but despite the presence of this pathology, maintain high cognitive and other functions.

Muna colleagues have deep expertise in the biology of resilience to neurodegeneration. We have identified brain cells that are key for maintaining resilience, and, within those cells, gene networks, signaling pathways, protein-protein interactions, and potential new drug targets.

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MiND-MAP: All-In-Human Target Discovery and Validation Platform

Muna’s all-in-human target discovery and validation approach, called MiND-MAP, uses single cell spatial multi-omics and bioinformatics analyses in unique cohorts of patient samples to focus on the genetic, molecular and cellular mechanisms that underlie resilience to disease pathology. We use this information to identify proteins potentially involved in resilience, and assess the role of these protein targets in human cells, humanized animal models, and patient tissue and biofluid samples.

Our in-house structural biology and computational chemistry toolbox allows us to rapidly identify and develop small molecules that modulate resilience targets and have potential to become future medicines.

Future Medicines To Change Disease Outcomes

Muna’s portfolio of disease-modifying small-molecule potential therapies includes two programs that address the functions of a key cell type, called microglia, which respond to and exacerbate neurodegeneration and compromise neuronal function. Our work, together with the work of scientists around the globe, suggests that normalizing the function of microglia may be an important aspect of brain resilience.

Our most advanced microglial-focused drug program, a best-in-class small molecule TREM2 agonist for early Alzheimer’s disease, is in Phase 1 clinical testing in healthy volunteers and elderly subjects. More information can be found here.

Other programs that address microglial and neuronal resilience are in early preclinical stages.

TREM2 Agonism for Alzheimer’s Disease

Our most advanced program is a small-molecule TREM2 agonist, MNA-001, with best-in-class potential for the treatment of early-stage Alzheimer's disease. MNA-001 is in Phase 1 clinical testing in healthy volunteers and elderly subjects. More information can be found here.

TREM2 is a key signaling node for microglial activation and modulates how these cells clear pathologic hallmarks of disease and preserve brain function. Genetic studies suggest TREM2 variants can be protective or risk factors for Alzheimer's disease, and microglial play central roles in disease. TREM2 agonism can enhance microglial function, resolving misfolded protein pathology and protecting neurons from degeneration. Muna's small-molecule compounds have excellent brain exposure following oral administration, exhibit high selectivity for TREM2, and have low concentration (single-digit nM) potency as agonists. Small molecules have a number of intrinsic advantages over antibodies for the treatment of neurodegenerative diseases that occur over several decades of life. Our small molecule TREM2 agonist MNA-001 has a different mechanism of action than the antibody which failed to demonstrate efficacy in a recent Phase 2 trial in Alzheimer’s disease, and is also different from other TREM2 antibodies which are currently in clinical development.

In animal models, our small molecules show excellent brain exposure following oral administration. In mouse models of Alzheimer’s-like pathology, treatment for three months with MNA-001 leads to a significant reduction in amyloid burden in the brain. In mice xenotransplanted with human iPSCs, TREM2 agonism activates xenografted human microglia, a process that is monitored with proprietary biomarkers from human cells. These biomarkers may translate into better monitoring in patients, allowing us to identify those most likely to benefit from our treatment.

Kv1.3 Blockade for Parkinson’s Disease and Multiple Sclerosis

Kv1.3 is a voltage-gated potassium channel and important regulator of microglia reactivity, the release of pro-inflammatory cytokines and chemokines, and of mitochondrial and other functions. Kv1.3 expression is upregulated in human brain and other cells in several disorders. Blockade of Kv1.3 with naturally occurring peptides and small molecule tool compounds is neuroprotective in rodent models of several neurodegenerative diseases, including Parkinson’s and Multiple Sclerosis. Understanding of Kv1.3’s role in microglia, neurons and other cells, together with strong evidence that Kv1.3 blockade can abrogate neuroinflammation and slow or stop neurodegeneration, support developing Kv1.3 blockers into future medicines.

Muna’s structural biology and protein chemistry capabilities enable us to identify small molecule candidate compounds that exhibit low concentration (single digit nM) potency, high selectivity for Kv1.3 compared to other Kv1 family channels, good oral bioavailability, and excellent brain exposure compared to other known Kv1.3 inhibitors. These small molecules are currently being optimized and tested in preclinical studies.