Neurodegenerative diseases such as ALS, Alzheimer’s disease, and Parkinson’s disease remain some of the most challenging disorders to treat. Despite decades of research, current therapies mostly manage symptoms rather than halt or reverse disease progression. Patients, families, and clinicians alike are seeking solutions that go beyond slowing decline, interventions that preserve function and potentially modify the course of disease.

Klotho Neurosciences, Inc. (NASDAQ: KLTO) is pioneering a gene therapy approach by leveraging the human Klotho gene, often referred to as the “anti-aging” gene, to create and develop novel gene and cell therapies. By delivering the secreted form of the Klotho protein (s-KL) directly to neurons, Klotho Neurosciences aims to protect, restore, and regenerate neuronal networks while addressing key biological drivers of aging and neurodegeneration. Drug Development & Delivery recently interviewed Dr. Joseph Sinkule, CEO of Klotho Neurosciences, discusses the company, its therapies, the human Klotho gene, and longevity.

Q: Can you tell us a little bit about Klotho Neurosciences and how your therapies work?

A: Klotho Neurosciences is a biogenetics company focused on pioneering the development of innovative, disease-modifying gene therapies using a patented, secreted form of the human Klotho gene, known as s-KL. This “anti-aging” gene was first identified in 1997 by Dr. Makoto Kuro-o, who showed that mice lacking the Klotho gene and the protein transcribed by the gene showed accelerated aging across multiple systems, including brain functions, muscle and bone loss, and vasculature calcification. The discovery was transformative and the  Klotho gene emerged as a master regulator of aging, influencing neuronal protection and survival, oxidative stress, mitochondrial function, autophagy, and neuroinflammation.

Our therapies at Klotho are designed to leverage these protective mechanisms. By delivering the Klotho protein via genetic or cell therapy, we aim to restore neuronal health, clear toxic protein aggregates such as beta-amyloid and TDP-43, reduce chronic inflammation, and stimulate neurogenesis and myelin production on axons that traverse from the brain down the spinal cord and ending at the neuromuscular junction. Importantly, our lead program, KLTO-202, is targeting ALS, a disease where motor neurons at the neuromuscular junction progressively degenerate and die, leading to muscle wasting and loss of voluntary and involuntary muscle movement. In preclinical models, our Klotho-based interventions preserved motor neuron function, strengthened muscle movement and electrophysiology endpoints, delayed disease onset, and improved survival.

Beyond ALS, we also see potential applications in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and other neurodegenerative or age-related conditions. The Klotho protein is naturally produced by neurons throughout the central nervous system, but its levels decline with age and low levels are found in disease states. By supplementing this essential protein therapeutically, we hope not only to slow disease progression but also to improve overall neuronal resilience, muscle and bone strength, and healthy aging.

Q: What is the significance of the Klotho gene, and where did its name come from?

A: The Klotho gene is one of the most important discoveries in aging and neurodegeneration research. In 1997, Dr. Makoto Kuro-o demonstrated that knocking out this gene in mice caused dramatically shortened lifespans and accelerated aging across multiple systems — including muscles, bone, blood vessels, heart, kidneys, and the central nervous system. In the brain, mice lacking Klotho expression exhibited memory deficits, hippocampal degeneration, reduced numbers of synapses, impaired axonal transport, severe neuroinflammation, and defects in CNS-protective myelin production.

Kuro-o named the gene “Klotho” after the Greek goddess Clotho, one of the Fates, who “spins the thread of life.” This gave rise to the gene’s enduring nickname, the “anti-aging gene.”

The Klotho gene actually produces two proteins. The membrane-bound form, m-KL, regulates phosphate and calcium balance in the kidneys by interacting with FGF-21 and FGF-23. The secreted form, s-KL, is particularly exciting for neurodegenerative diseases. It is produced mainly in the human brain and protects neurons from oxidative stress, enhances mitochondrial energy functions, reduces inflammation, enhances autophagy or the clearance of senescent cellular debris, improves synaptic plasticity and axonal transport, stimulates neurogenesis, and promotes myelination of axons in the spinal cord. These combined effects translate into better cognition, memory, and motor function in preclinical models.

Q: How do you see Klotho Neurosciences addressing the underlying biology of ALS and other neurodegenerative diseases?

A: Aging is the largest risk factor for neurodegeneration. As we age, DNA damage accumulates, mitochondrial function declines, autophagy slows, and inflammation becomes chronic. These processes drive neuronal death and synaptic dysfunction.

As noted, Klotho acts at multiple points along these pathological pathways. It protects neurons from oxidative stress, enhances autophagic clearance of toxic proteins, stimulates neurogenesis, and modulates inflammatory signaling. In ALS, for example, Klotho preserves motor neurons, helps to generate new motor neurons, and facilitates s the flow of neurochemicals across the neuromuscular junction, which is critical for muscle function. By intervening early, our therapies could restore or maintain neuronal signaling and slow ALS disease-associated pathologies and progression.

Our approach allows us to bridge the gap between the abstract concept of healthy “longevity” and the tangible clinical outcomes patients care about that include stable or improved motor function, muscle contraction, cognitive preservation in the brain, and an extended quality of life.

Q: KLTO-202 has received Orphan Drug Designation for ALS. What are the next milestones in your clinical and regulatory pathway?

A: KLTO-202 is our lead candidate, and we’re progressing toward Phase 1B/2A trials in early ALS patients. Our immediate milestones include completing manufacturing and IND-enabling studies this year, followed by filing the IND in Q4 2026 or Q1 2027. Once the IND is approved to begin clinical trials the adaptive design clinical trial will leverage Fast Track designation and Breakthrough designation to accelerate development.

We’re also advancing KLTO-101 for delivery of the gene to the brain to treat Alzheimer’s, Parkinson’s, and other neurodegenerative indications, with IND submission planned in mid-2027 and initiation of the trial later that year. Meanwhile, KLTO-301, a Klotho gene variant that makes a full-length m-KL protein, will target cardiovascular and chronic kidney diseases, which illustrates the broader potential of Klotho across multiple organ systems.

These programs are supported by strategic partnerships with leading contract manufacturing and adeno-associated virus (AAV) delivery organizations to ensure high-quality production and tissue-targeted delivery. Our goal is to move efficiently from preclinical success to human trials while maintaining rigorous safety and efficacy standards.

Q: The Klotho gene influences multiple biological systems. Do you see it more as a systemic longevity factor or for targeted disease-specific applications?

A: Both perspectives are valid, but from a clinical development standpoint, we focus on targeted applications first. If we can effectively treat several “diseases of aging”, we will effectively promote a longer, healthy lifespan. Trying to prove claims of improving longevity or life-span extension in humans is extremely challenging as such studies would need to track thousands of participants over decades of time, which is not feasible for development and regulatory approval and commercialization.

That said, the Klotho gene does impact multiple tissues like the brain, kidneys, cardiovascular system, muscles, and more, so the therapeutic effects we see in one disease could translate to broader benefits. Our primary aim right now is to treat neurodegenerative ALS, Alzheimer’s disease, and Parkinson’s disease, where the unmet need is critical and where preclinical efficacy is strongest. The endpoints for market approval by the regulatory authorities is also well established for these diseases. As we gather more clinical data, we anticipate exploring additional age-associated conditions. In this way, Klotho Neurosciences could eventually serve both as a disease-specific therapy and as a systemic enhancer of healthspan.

Q: Klotho research is rapidly expanding. How do you anticipate its role in the broader longevity or geroscience field in the next decade?

A: Klotho is already recognized as a key longevity factor, and research is growing exponentially with over 4,000 publications on Klotho biology since 1997. In the next 10 years, I hope the scientific community will fully appreciate its role as a “master gene” regulating multiple pathways that influence aging and diseases of aging.

From a therapeutic standpoint, we envision Klotho-based treatments not only for specific diseases but also as tools to enhance biological resilience in aging populations. Our epigenetic blood test, which measures the Klotho promoter’s methylation status, could allow personalized interventions based on an individual’s epigenetic biological age, and with a single intravenous infusion of a long-active gene therapy, potentially slow the rate of age-related decline.

Ultimately, our goal is to transform the treatment paradigm for neurodegenerative diseases while laying the foundation for broader applications in longevity medicine.