The Klotho gene is an important “anti-aging” gene that encodes a transmembrane protein, primarily produced in the kidneys and brain, which acts as a circulating hormone to suppress aging, regulate mineral metabolism, and protect organs. Although it has been pinpointed by scientists, how can the properties of this gene be introduced into medicine?
To gain a scientific insight, Digital Journal spoke with Dr. Joseph Sinkule, Founder, Chief Executive Officer, Director and Chairman of the Board at Klotho Neurosciences. Klotho is a biogenetics company pioneering the development of innovative, disease-modifying cell and gene therapies using a patented, secreted form of the “anti-aging” human Klotho gene.
With a core focus on enhancing human longevity, the Company is dedicated to transforming and improving the treatment of neurodegenerative and age-related disorders such as ALS, Alzheimer’s disease, and Parkinson’s disease.
Its lead product candidate, KLTO – 202, which targets ALS and other neuromuscular diseases, has received Orphan Drug Designation from the FDA.
Digital Journal: Can you share a brief overview of Klotho Neurosciences and what inspired its founding?
Joseph Sinkule: A few years ago, I consulted for a fellow who had polycystic kidney disease and he asked me to find a manufacturer of the Klotho protein to treat his kidney disease under a Compassionate Use IND. As I dove deeper and deeper into the literature, I discovered a tremendous body of literature on the human Klotho gene and its two protein isoforms. As a serial entrepreneur, I formed a company, licensed a series of assets in the Klotho patent and R&D space, took the company public on NASDAQ, and raised money to support the gene and cell therapy approach for treating a variety of human diseases affected by the systemic, time-dependent loss of the Klotho protein over time in humans.
DJ: For those unfamiliar with it, what is the Klotho gene?
Sinkule: The gene was discovered in 1997 by Dr. Mako Kuro-O, MD, PhD. The Klotho gene sequence is found in all mammals. The gene sequence differs only slightly between human, mice, dogs, non-human primates, and so on. In humans, chromosome 13 contains the Klotho sequence. The gene consists of five exons that encodes a mRNA that makes a 140 KiloDalton (KD) protein in all cells of the body, but mainly in the epithelial cells of the kidney. The 140 KD protein is an obligatory co-receptor for FGF-21 and FGF-23, such that the protein and FGF-23/21 binds to the FGF receptor and controls phosphate and calcium homeostasis in our body.
After sequencing the human gene, a TAA “stop signal” on exon 3 of the Klotho gene was discovered which led to the acknowledgment that the Klotho gene produced two isoforms of the protein – the 140 KD protein and a smaller 63 KD protein called secreted Klotho or s-KL. It was later discovered that the s-KL protein is predominantly produced in the choroid plexus and hippocampal regions of the human brain. The s-KL does not bind FGF, as the FGF binding arm is only contained on the full-length, 140 KD protein. Our intellectual property is focused on the protective and stimulatory capacity of the s-KL isoform in the brain and central nervous system (CNS) in general.
DJ: Could you tell us about your lead therapeutic candidate and the diseases it’s targeting?
Sinkule: We have two therapeutic candidates under development – KLTO-101 and KLTO-202. KLTO-101 uses an adeno-associated virus vector (AAV.bbb) that crosses the blood-brain-barrier and provides a novel s-KL gene and promoter sequence to the neurons in the brain. KLTO-101 targets any neurodegenerative pathology of the brain and spinal cord, such as Alzheimer’s, Parkinson’s, Huntington’s and other neuropathologies of the brain induced by interfering communication between neurons or death of the neurons from neuroinflammation.
KLTO-202 uses an AAV.myo that targets neurons and the junction between neurons and muscle cells – delivery to the neuromuscular junction. KLTO-202 carries a muscle-specific promoter driving expression of the s-KL protein at the interface between muscle and brain. KLTO-202 targets amyotrophic lateral sclerosis (ALS, motor neuron disease (MND), or Lou Gehrig’s disease) and several other motor neuron diseases like muscular dystrophy, spinal muscular atrophy and multiple sclerosis.
DJ: What key milestones can we expect from Klotho this year?
Sinkule: The key milestones of 2026 include finalizing the GMP manufacturing and QC testing of KLTO-101 and KLTO-202 so that both candidates can be released for the start of clinical trials. Once the initial batches have been produced, we will meet with regulatory authorities in the major markets and disclose our development plans and “target product profile” of KLTO-101 and KLTO-202. We will also evaluate the availability of
Compassionate Use or “Early Access” programs in the US, China, France and Australia whereby we can administer a single dose of KLTO-101 or KLTO-202 to certain patients under these “early access” protocols and follow them for efficacy endpoints and safety monitoring. This “early access” effort will likely focus on KLTO-202 in patients with the definitive diagnosis of ALS.
DJ: Where do you see cell and gene therapy heading in the next five years?
Sinkule: Our Team believes gene and cell therapies are the future of medicine. Gene and cell therapies can replace a depleted source or mutated source of proteins that are essential for life. When genes are deleted, mutated, or “silenced” through an aging process called DNA methylation, essential proteins need to be replaced.
With gene and cell therapies, we can produce those essential proteins inside the patient’s body. Wouldn’t it be great to administer a single dose of medicine that makes a protein inside the body for long periods of time. Such an approach would be ideal for improved patient compliance, improved outcomes, and tremendously reduced health care delivery costs.
