Mitokor Inc.

Diagnostics and Therapeutics based on mitochondrial function. MitoKor studies the DNA found in mitochondria to link diseases to mutations in mitoDNA, and suggests a connection between mitochondrial defects and Alzheimer's and Parkinson's disease.

Tracking and treating diseases via the "other" human genome.

• 11494 Sorrento Valley Road

• San Diego, CA 92121

• Phone: [phone]

• Fax: [phone]

• Contact: Walter H. Moos, PhD, CEO and Chairman

• Industry segment: Pharmacogenomics

• Business: Diagnostics and therapeutics based on mitochondrial function

• Founded: 1992

• Founders: W. Davis Parker Jr, MD, Dean Cuplin

• Employees: 30, plus 15 academic collaborators

• Financing to date: Over $30 million ($16.1 million received in June, 1997)

A few years ago, when Robert Davis, PhD, the president and chief scientific officer of MitoKor Inc. (then called Applied Genetics Inc.) was introduced at genomics conferences, his colleagues would refer to him as "the guy working on the stuff we throw away." Whereas most genetic researchers look for clues to disease in the stretches of DNA coiled in the nuclei of higher cells, Davis and his colleagues at MitoKor study the DNA found in mitochondria, which exist outside the nucleus in the cellular cytoplasm. Mitochondria convert glucose and oxygen into cellular energy in the form of adenosine tri-phosphate, or ATP. Despite this vital role as cellular power plants, mitochondria have been given short shrift by most researchers, perhaps because of their etiology.

Mitochondria are thought to be descended from a bacterium-like organism that billions of years ago began living in symbiosis within more complex cells. Through eons, they have kept some of their own genes intact. Mitochondrial DNA (mitoDNA) exists as a double-stranded ring with a relatively short chain, distinct and separate from the long double-stranded helix of nuclear DNA (nDNA). There are other notable differences. Cells contain only two copies of nDNA, but they contain large numbers of mitochondria, quantity generally being related to the cell's energy needs. A single neuron, for instance, can contain 1,000 to 2,000 mitochondria. While nDNA is inherited from both parents, mitoDNA is inherited from the mother only.

"For a long while, it was almost like people were thinking the nuclear DNA was their only inherited genetic material, like the mitochondria were just something else," says Walter H. Moos, PhD, who came to MitoKor as its new CEO and chairman in January from Chiron Corp. where he was VP, R&D. Lately, scientists and investors alike are looking at MitoKor's research focus in a whole new light. In April, MitoKor published a peer-reviewed study in the Proceedings of the National Academy of Science that showed approximately 60% of 506 patients diagnosed with "probable Alzheimer's" had high levels of mutations in their mitoDNA. MitoKor believes high levels of mutations in the gene coding for a mitochondrial enzyme complex not only decrease energy metabolism in the brain, but also cause production of so-called oxygen-free radicals. These damaging molecules may be key to Alzheimer's disease pathology.

Moos says MitoKor now has data from some 2,000 people diagnosed with probable Alzheimer's disease, and the findings are holding steady: 60-70% of patients have mitoDNA mutations. Tests of children with affected mothers and fathers turned up significantly higher rates of mutations in the offspring of affected mothers, but not affected fathers, further supporting the mitochondrial connection, the company reported. The good news, Moos says, is that the mitochondrial enzyme deficiency is likely to be treatable with small molecules that would also suppress generation of oxygen-free radicals. Vitamin E captures these free radicals on a one-to-one basis, but MitoKor believes a far more efficacious agent will be needed to counteract the high quantities of these molecules present in diseased neural tissues.

The company has already begun testing people enrolled in clinical trials of anti-dementia drugs for mitochondrial mutations on behalf of two major pharmaceutical companies, who hope the diagnostic information will help them cull and stratify patients. The idea is to pick out patients most likely to respond to a drug from those who probably won't benefit, perhaps even determine whom a drug might harm, and so improve outcomes for the population of patients that do make the cut. This diagnostic to measure the relative amount of mutated versus normal mitoDNA (the mitochondrial "load") could then also be used to monitor patients to see whether and how well drugs or lifestyle changes are working.

"Bill Rutter [Chiron's chairman] had this great vision to prevent, diagnose, treat and monitor disease, and he blazed the trail for the rest of us to follow," Moos says. Chiron trade-marked the concept Therametrics, a word that Moos also uses to describe what MitoKor hopes to do outside of the infectious-disease area Chiron has already claimed. Just as Chiron patented its viral-load diagnostics, MitoKor has applied for patents on its methods of measuring mitochondrial load. Beyond Alzheimer's, MitoKor's studies are also beginning to suggest a connection between mitochondrial defects and Parkinson's disease. Non-insulin dependent diabetes mellitus may also be linked to mutant mitoDNA, MitoKor believes.

"As far as I can tell, mitochondria are the last untapped frontier in genomics," Moos declares. He reckons that MitoKor will eventually have to bring in other technologies, but for now he's concentrating on building a strong therapeutics R&D program, plus a diagnostics business to generate cash flow and provide operational strength. "Today, we can probably generate anywhere from $1-10 million in revenues from the Alzheimer's diagnostic. That's not a lot, but it's an information-only research product at this point." If MitoKor's test does prove capable of stratifying patients, Moos believes it could be a $100 million product. For now, he's thinking about pricing the diagnostic in line with brain-imaging test batteries such as CT scans and MRIs, which can cost $500 to $1,000 per test.

"If you can confirm a diagnosis of Alzheimer's (now possible only by autopsy), you may be able to start moving some of this testing back to the internist," Moos asserts. If MitoKor can in fact confirm diagnoses, it would like to see its test deployed earlier and earlier, to catch people before they progress to later stages of the disease, or before they develop it, "perhaps even back to the egg," Moos says. He expects the firm's test to confirm diagnosis absolutely in at least 20% of cases, where the mitogenome loads are much higher than the general population.

MitoKor intends to continue supporting clinical trials of anti-dementia drugs with its mitoDNA diagnostic, mostly through Big Pharmas, and some through academic collaborators. But the company is also looking to collaborate with major reference labs, to begin using the tests for research purposes only, in hopes of generating good data and consequently, buy-in from the medical community. Rather than license away its test to a major diagnostic company, MitoKor hopes to earn a higher margin of return on its innovation by establishing a vertically-integrated joint venture, similar to the one Chiron did with Ortho Diagnostic Systems Inc. for immunodiagnostics.

Moos expects MitoKor will see competition from other companies just now beginning to commercialize their own research of mitochondria, but neither he nor the company's investors are overly worried. As venture capitalist Arthur Klausner of Domain Associates puts it: "We believe in backing first and dominant companies, and MitoKor is that in its field." Still, firms such as Eukarion Inc. , working in collaboration with Glaxo Wellcome PLC [See Deal], and Avicena Inc. in Cambridge, developing mid-sized molecules that could affect biochemical cycles, are two outfits to watch. They too could develop therapies that influence the "other" human genome.

Walter H. Moos, PhD, is the CEO and chairman of MitoKor; previously he was for five years corporate VP and VP, R&D at Chiron Corp., and before that, VP, neuroscience and biological chemistry at Parke-Davis Pharmaceutical Research, a division of Warner-Lambert Co. Robert E. Davis, PhD, is president and chief scientific officer. Michele L. LeGear is VP.

MitoKor's original investors include El Dorado Ventures, SR One Limited, funds managed by MDS Health Venture Capital Corp. and others. In May 1996, the company celebrated a re-start with $10.6 million in venture financing led by Alta Partners [See Deal].--DE