KeyNeurotek Pharmaceuticals reports breakthrough discovery in Huntington's Disease
KeyNeurotek Pharmaceuticals reports breakthrough discovery in Huntington's Disease / Company elucidates molecular pathomechanism of Huntingtin mutation
Huntington's Disease is a rare neurodegenerative disease of the human brain leading to uncontrolled movements, emotional disturbance and finally to loss of intellectual faculties. Patients usually die within 15-20 years after the onset of first symptoms. On the molecular level, it is characterized by a mutation in the so-called huntingtin gene which leads to a protein with an abnormally increased number of glutamine residues (httexpQ). The underlying pathomechanisms linking this mutation to the origination and progression of Huntington's disease, however, had remained unclear for more than a decade.
Now researchers at KeyNeurotek and its long-term collaborators at the Universities of Erlangen-Nuernberg and Tuebingen (both Germany) have discovered that httexpQ specifically targets certain transport proteins of brain mitochondria. Using a new proprietary transgenic rat strain, which was generated by Prof. Stephan von Horsten and which for the first time models the adult form of human Huntington's Disease, the authors identified the so-called mitochondrial glutamate/aspartate carrier (aralar) and the permeability transition pore as specific targets of httexpQ.
In addition, the researchers found that Ca2+-dependent substrate supply and consumption of brain mitochondria become severely compromised, if httexpQ interferes with its targets. Mitochondria serve as cellular power stations consuming oxygen and appropriate substrates to supply the extraordinary energy demand of neuronal brain cells with sufficient amounts of energy equivalents (ATP). Therefore, httexpQ-induced inhibition of substrate influx and ATP generation severely impairs brain mitochondria and causes a sequence of devastating events which are crucially involved in the progression of Huntington's Disease, i.e. mitochondrial dysregulation, energetic depression, neuronal cell death and tissue atrophy.
"After 15 years of research on the cytotoxic actions of mutated huntingtin, these findings for the first time not only provide a new basis for the understanding of Huntington's Disease but also for the development of a causal treatment", said Dr Frank Gellerich, Head of the Department of Energy Metabolism at Keyneurotek and lead author of the study. "This breakthrough discovery has been possible thanks to a long-standing and productive collaboration with our academic partners in Erlangen and Tuebingen."
"These findings once again underline our strong research capabilities and our expertise in CNS-related diseases", Dr Frank Striggow, CEO of KeyNeurotek Pharmaceuticals added. "Besides, the energy metabolism is key to understanding other chronic CNS diseases, e. g. Alzheimer's and Parkinson's Disease, and ageing. We therefore believe that our research provides us with various opportunities for the development of novel treatment strategies in the area of neurodegenerative diseases."
About Huntington's Disease
Huntington's disease (HD) is a rare inherited neurological disorder (3 to 7 per 100,000 people), usually occuring in patients at middle age . Early symptoms of HD are mood swings, depression, irritability or trouble driving, learning new things, remembering a fact, or making a decision. As the disease progresses, concentration on intellectual tasks becomes increasingly difficult and the patient is suffering from involuntary movements and severe mental deterioration. The disease ultimately leads to death within 15-20 years after the onset of the first symptoms.
HD is caused by a defect in a single gene, the so-called huntingtin gene. The gene is dominant, so that each child of a HD patient has a 50:50 chance of inheriting the disease.
In HD patients, the gene contains an increased number of a so-called trinucleotide repeats, i.e., the genetic code is "stuttering". Since the discovery of the gene and its abnormality in 1993, an accurate diagnosis has been developed., However the disease cannot be treated, although there is a number of medications available to alleviate some of the symptoms.
As the first symptoms of HD usually occur in middle age patients, it is likely that affected people already have passed the gene on to their children.
The huntingtin (htt) gene involved in Huntington's disease was discovered in 1993 and is located on the human chromosome number 4. Even in its normal form, it carries a trinucleotide repeat, i. e. the sequence of the three DNA building blocks cytosin-adenin-guanine (CAG) is repeated several times. Less than 36 CAGs in a row are normal; but if their number is 36 or above, the protein causes neurons to die.
Interestingly, counts of 36-39 CAGs result in a later onset of the disease and slower disease progression, while counts above 39 result in early onset and fast disease progression.
As the altered gene is passed from one generation to the next, the number of CAG repeats can change; it often increases in size, so that subsequent generations have an earlier onset and more severe disease than their parent they inherited the gene from.
Despite its discovery 15 years ago, the exact function of the htt gene is still unknown. The gene encodes for a protein, the so-called Huntingtin protein, which is highly expressed in neuronal cells, where it is found in association with certain cell structures such as vesicles, microtubules, and mitochondria.
KeyNeurotek Pharmaceuticals AG
KeyNeurotek Pharmaceuticals, a privately held biotechnology company, was founded in 2000 within the Magdeburg, Germany, region, one of the leading centres of neuroscience in Europe.
The company pursues a number of drug candidates in various preclinical and clinical stages. The most advanced compound, KN38-7271, a cannabinoid receptor agonist, is in a Phase IIa trial in comatose patients with traumatic brain injury. At present, there is no targeted therapy for these patients.
KeyNeurotek Pharmaceuticals has unique functional and tissue-based high throughput screening platforms for compatible ex vivo and in vivo studies (TELOMICSTM). Based on its know-how, KeyNeurotek develops innovative therapies for the treatment of various neurodegenerative diseases of the central nervous system, such as traumatic brain injury (TBI), stroke, Alzheimer's disease and urinary incontinence/overactive bladder.
The company has built a strong network with renowned local and international partners, including, among others, the Leibniz Association, the Max Planck Society and Fraunhofer Society, Evotec, Schwarz Pharma/UCB, Bayer Schering and Gruenenthal. KeyNeurotek has been awarded the Hugo-Junckers Innovation Award of the State of Sachsen-Anhalt in 2002 and 2004 and the Innovation Award of the German Industry in 2006.