In the Department of Neurology at NewYork-Presbyterian/
Michio Hirano, MD, Chief of the Division of Neuromuscular Disorders and Director of the H. Houston Merritt Neuromuscular Research Center at Columbia, primarily focuses his practice and his research on rare diseases and, in particular, on a subgroup of patients with genetic mitochondrial diseases and genetic myopathies.
Dr. Michio Hirano
“Mitochondrial diseases are uncommon and collectively affect an estimated 1 in 5,000 people. But there are many subtypes of these diseases, and some may affect just one in a million people,” says Dr. Hirano, who is also the Lucy G. Moses Professor of Neurology and Director of the MDA Care Center at Columbia. “They affect people of all ages from infants through late-adulthood and can present with one symptom or involve multi-systemic diseases. The average number of symptoms per patient is 16.”
“These rare mitochondrial diseases are not well known in the medical community,” continues Dr. Hirano. “Very often patients are referred to us by primary care physicians or general neurologists who recognize that their patients have a neuromuscular problem, but don't know specifically which type. We conducted a survey recently and found that, on average, patients were seeing more than eight physicians to get to their diagnosis of mitochondrial disease. One of our missions as clinicians is to expedite and end that diagnostic odyssey. To achieve that, we provide highly specialized, comprehensive evaluations that can involve biochemical, histological, and DNA analyses.”
By collecting detailed information on each patient through that diagnostic process, Dr. Hirano and his colleagues developed a clinical registry to help direct their investigations to characterize these diseases and the mechanisms by which a mutation might cause nerve and muscle dysfunction. This database transitioned to become the foundation of the North American Mitochondrial Disease Consortium (NAMDC), an NIH-sponsored consortium with 16 sites across North America that contribute patient data to the registry. The NAMDC is a collaboration with the United Mitochondrial Disease Foundation, the leading patient advocacy group in the country for these diseases.
By collecting detailed information on each patient, Dr. Hirano and his colleagues developed a clinical registry to help direct their investigations to characterize these diseases and the mechanisms by which a mutation might cause nerve and muscle dysfunction.
“The NAMDC registry contains a tremendous amount of information about patients’ clinical manifestations and their genetic, biochemical, and neuro-imaging features,” says Dr. Hirano, who serves as the Principle Investigator of the NAMDC. "We share that, of course, with everyone in the NAMDC consortium, but it is also available to external groups to data mine and learn from as well. Combining patients enables greater insight into the spectrum and natural history of the disorders, provides a DNA and cell bank resource, and houses a pool of potential patients for upcoming open trials. We also have a biorepository with blood and skin biopsy samples that is shared with both academic and commercial investigators. This is a team effort to advance knowledge and ultimately develop therapies for mitochondrial diseases, which individually, each is rare, but collectively they are among the most common neuro-genetic disorders in the general population.”
Making Sense of Mitochondrial Genetics
Inherited defects causing mitochondrial dysfunction can be due to mutations either in nuclear DNA (nDNA) or in mitochondrial DNA (mtDNA). “Since there are numerous copies of mtDNA per cell, depending on the percentage of mutated genomes and their distribution in the various organs, mtDNA mutation syndromes vary in their severity,” explains Dr. Hirano. “In the laboratory, we are applying viral vector delivery of gene therapy to replace mutant nDNA genes in mouse models. We are also investigating a new technology called antisense oligonucleotides, or ASOs, which are targeted to block the expression of some of these mutations and may have therapeutic potential for patients.”
Dr. Hirano notes a case in point involving Darryl C. De Vivo, MD, and Claudia A. Chiriboga, MD, colleagues in the Child Neurology division at Columbia, who conducted clinical trials with an antisense oligonucleotide for spinal muscular atrophy. “They have been leaders in an international effort to develop this therapy – a drug called Spinraza™ – that is now approved for children with this very severe and often lethal disease,” says Dr. Hirano. “This is one example where a treatment has been started in the laboratory and taken through clinical trials to commercial implementation.”
Dr. Hirano, Hasan Orhan Akman, PhD, Associate Professor of Neurology, and their research team are currently working on an antisense oligonucleotide therapy for a particular mutation that causes adult polyglucosan body disease (APBD), which predominantly affects people of Ashkenazi Jewish background. This ultra-rare mutation affects fewer than 30 people in the world. “This is a late onset neuromuscular disease in which patients develop spasticity, urinary dysfunction, and peripheral neuropathy that is very debilitating,” says Dr. Hirano. “Many of these patients are wheelchair bound in their 50s or 60s. Because there is a recurrent mutation in the Ashkenazi Jewish population that is amenable to antisense oligo therapy, we are working with the n-Lorem Foundation to develop this therapy to target this particular mutation.” Dr. Akman has already tested a number of ASOs in cells of patients and has demonstrated that they can correct the genetic defect. In addition, Dr. Akman has developed a mouse model for APBD that can be used in experiments to understand the mechanism of the disease and to test certain pharmaceuticals that can cure or eliminate symptoms.
A Translational Success for TK2 Deficiency
Thymidine kinase 2 (TK2) deficiency is another rare inherited mitochondrial disease affecting several hundred people worldwide. The autosomal recessive condition presents predominantly as a myopathy, which can develop in infancy through adulthood, although the majority of cases begin in childhood. “This is a progressive muscle disease causing weakness of limb, swallowing, and respiratory muscles,” notes Dr. Hirano. “It's relentlessly progressive, and patients, especially those with the early-onset forms, die very early in life.”
Dr. Hirano and his colleagues have been studying TK2 deficiency in a mouse model in which the mouse recapitulates the infantile-onset disease. The researchers were able to reproduce the mitochondrial DNA depletion and mitochondrial dysfunction. “Onset of growth retardation was demonstrated at 10 days and weakness was evident in the second week of life,” says Dr. Hirano. “These mice generally died in the third week of life. So it's a very severe disease in the mice as it is in the infantile-onset form of the human disease. We have been developing a deoxynucleoside therapy, whereby we give the substrate for the TK2 enzyme and it bypasses the biochemical block in TK2, presumably through another enzyme called TK1. In the mouse model, this approach delayed the onset of symptoms and extended the life of the mice two- to three-fold in a dose-dependent fashion. We have also started to administer this therapy to patients, initially under compassionate-use or expanded-access protocols, both in the United States and in Spain. The therapy is now being tested in a phase II trial and is expected to proceed to the Food and Drug Administration with a New Drug Application next year.”
“This treatment program has moved very quickly though the pipeline from the few initial patients we began using the therapy with about 10 years ago to now, where there's an ongoing phase II trial with planning for the phase III trial underway,” says Dr. Hirano. “It’s very exciting. The treatment has made a tremendous difference, especially in the young patients who started it early in their disease course. We’ve had selected success, where some young children who had lost the ability to sit and stand have now regained the ability to walk and to run. A few of the patients have also come off of ventilators.”
An Exclusive Gene Transmission by Mothers
Mitochondria have their own DNA, and that genetic material is transmitted exclusively from mothers to their children. There are many individuals who suffer from a variety of mitochondrial diseases because of mutations in that mitochondrial DNA. Dr. Hirano, in collaboration with Dieter Egli, PhD, Assistant Professor of Developmental Cell Biology (in Pediatrics) at Columbia and a world-renowned stem cell biologist, are exploring a very novel mitochondrial replacement technique to prevent the transmission of those mitochondrial DNA mutations.
Through the Columbia University Fertility Center, Dr. Egli has been collecting eggs from women who have mitochondrial DNA mutations. “He can extract the nucleus from that egg and transfer that nucleus into the cytoplasm of a healthy oocyte without a mitochondrial DNA mutation…in other words, it's combining the nuclear DNA of the mother with the mitochondrial DNA from a donor egg,” explains Dr. Hirano. “We are replacing the organelle, including the DNA, but we're not manipulating the DNA in any way. This technology would allow the biological mother and father to have children with their nuclear material, but healthy mitochondrial DNA from a donor.”
“We are at a significant juncture in our understanding of mitochondrial diseases and promising therapeutic opportunities,” says Dr. Hirano. “We have come a long way with a group of rare and ultra-rare diseases that were genetically undiagnosable a little over three decades ago. We have identified exact molecular mechanisms and are now developing very specific, targeted, precise therapies.”
