GNE Myopathy was described by Ikuya Nonaka in 1981 in Japanese patients. Almost simultaneously the same disease was reported by Zohar Argov in 1982 in Israel amongst Jews of Persian origin. It was called quadriceps sparing myopathy (QSM) after it was noticed that in these patients the quadriceps were remarkably spared. Two strong international groups for research in this disease were thus created. The Israeli group in 1996 and the Japanese group in 1997 after extensive experimentation established that the disease was caused due to mutations in a gene whose approximate location on human chromosome number 9 was revealed, but (since there are many genes close by) the affected gene was still unknown. In 2001, this gene was finally identified by Stella Mitrani-Rosenbaum’s group as GNE. We now know that GNE sequence variants are found not only amongst the Japanese and Persian Jewish populations but are seen in highly diverse ethnicities amongst patients from Asia, Europe, Africa and the Americas. Many names have been used to describe this disease, including hereditary inclusion body myopathy (HIBM), or inclusion body myopathy 2 (IBM-2). To avoid confusion it has now been accepted that the disease will be referred to as GNE Myopathy.
GNE Myopathy is a recessive disease, that is, it is caused when both copies of chromosome 9 in the patients carry a mutated version of GNE. The mutations do not cause complete loss of GNE protein function, as that may be lethal, as seen in the mouse model that was created with GNE mutations to study their effect. Rather, the activity of GNE leading to sialic acid production is reduced and is low enough to manifest as myopathy in adult life. Sialic acid is a sugar that attaches itself to many proteins in each cell. This process is called sialylation and is necessary for these proteins to perform their designated functions. Reduced sialylation is probably a major cause of GNE Myopathy as administration of sialic acid or its precursor ManNAc, could arrest the development of disease in the mouse models. However, the picture may not be that simple. Functions of GNE protein other than sialic acid synthesis could also be involved. It has been found that GNE protein interacts with many other proteins of the cell including those from cytoskeleton and mitochondria. Expression of mutant GNE proteins can lead to enhanced apoptosis, mis-localization of proteins within the cellular compartments and defect in signalling and interaction with other cells. All these can explain observed phenotype seen in patients. We need to understand the nature of molecular mechanisms underlying pathobiology of the disease in order to develop proper therapies for GNE Myopathy. Preliminary results obtained from clinical trials based on sialic acid and ManNac supplementation indicate lack of significant improvement or even complete arrest of progression of the disease, suggesting that the phenotype seen may be due to defects in pathways other than that of sialic acid.
Gene editing means changing the DNA sequence of an organism (such as human) in situ, that is, within a living organism. This technology has the potential to change any sequence (like a mutation) in a patient’s DNA and convert it back into the normal sequence . Several types of gene editing methods have been developed in the last decade. However, a major discovery made public three years back by Profs Jennifer Doudna of University of California, Berkeley and Emmanuelle Charpentier, now at the Helmholtz Centre for Infection Research in Germany, changed this field, opening up the possibility of successfully carrying out gene editing in whole animals. They discovered a cheap and efficient new system for editing DNA. Known as CRISPR-Cas9 it has been adopted by scientists around the world. CRISPRs (clustered regularly interspaced short palindromic repeats) are short segments of DNA, while Cas9 (Crispr-associated protein 9) is an enzyme. They are found in bacteria as a defence system against attacks from viruses. CRISPR sequences code for short RNAs called guide RNAs which scan the genome looking for their matching sequences and then use the Cas9 protein as molecular scissors to snip through the DNA. The faulty DNA is cut out and may be replaced with a piece of normal DNA. The technique is cheap and highly precise, a major advantage for use in human system.
Each organ of our body is made up of cells that are designed to carry out their own specialized function. Thus, cells of bone are different from those of muscle or blood and so on. But all of these different cell types were originally derived from very similar cells during our development in the womb right up to adulthood. These cells are called stem cells.
A stem cell is a cell that can multiply by division, and in response to some stimulus can differentiate (convert) into a specialized cell-type of a particular tissue/organ. Stem cell numbers are very high in the fetus but drop in the adult as development is complete and no more differentiation is required. However some stem cells are present in the adult to help in replacement of dead cells and regeneration of damaged tissue. These cells can be an attractive source for therapy as they are derived from the same individual.
Ever since it became clear that stem cells could be used to replace damaged tissues in patients there have been concerted efforts world-wide to develop appropriate technologies to harvest the potential power of stem cells. The field has seen monumental advances in the last two decades. Basically the need is to have stem cells in sufficiently large numbers, which would differentiate into the organ of one’s choice, would not be rejected by the host, and would not show adverse effects (like tendency to form tumors). It is therefore important to have definitive clinical studies to demonstrate efficacy of each stem cell therapy before it can be tried with patients.
Embryonic stem cells (obtained from embryos) are one of the best sources of pluripotent stem cells (that is, they can differentiate into any tissue); however it is not always possible to get these due to various issues, including ethical ones. They could also sometimes lead to tumors. Adults also contain stem cells in their tissues- although their numbers are low. Bone marrow is used as a source of adult Mesenchymal stem cells. These can differentiate into a variety of tissues like bone, muscle, nerves, cartilage, ligament, tendon, fat, blood cells. A limitation in their use is their typically low numbers.
Induced pluripotent stem cells (iPSC) can be generated in the lab. As their name suggests, they can be induced to form, by coaxing a small amount of skin tissue from an adult to form stem cells. These can further be converted into specialized cells like nerve and muscle cells. Due to the potentially vast application of this technology to convert any cell into a stem cell it fetched the Nobel prize to its inventor (Shinya Yamanaka from Japan).
A major limitation in the use of stem cells is connected to the amount and quality of cells that can be generated using current technology. These bottlenecks have hampered initiation of large scale clinical trials. Cynata Therapeutics Ltd. (CYP:ASX) in association with University of Wisconsin have announced breakthrough technology for large scale generation of stem cells through iPSC pathway. Their innovative manufacturing methods can generate robust, consistent and inexpensive stem cells particularly mesenchymal stem cells (MSC), and this will allow likely commercialization of stem cell therapies worldwide for a group of diseases and pave the way to develop manufacturing technologies for other stem cells (http://www.thelifesciencesreport.com/pub/na/delivering-the-triple-whammy-that-makes-stem-cell-therapies-commercially-viable-cynata-therapeutics-ross-macdonald)
Stem cells are also present in adult tissues, so that any injury or damage can be taken care of immediately by these cells. In general the pool of classical stem cells gets depleted in severe injury or muscle damage due to disease, causing problems in natural repair process. Satellite cells dotting muscle fibers have always been thought to have stem cell like function and studies carried out in mice do suggest their usefulness in muscle regeneration. However, their existence in human was not clear. Recently a research group at the University of California has identified and characterized human muscle satellite cells and shown their stem cell like properties paving the way for possible therapy for injury and myopathy (http://www.thestatesman.com/news/science-and-tech/human-muscle-stem-cells-isolated/93380.html)
A recent technological breakthrough enables the use of adipose (fat) derived stem cells in place of bone marrow. Autologous stem cells from a person’s own fat are easy to harvest safely under local anesthesia and are abundant in quantities- up to 2500 times those seen in bone marrow. When these adipose derived stem cells are administered back in to the patient, they have the potential to repair tissues by forming new cells of mesenchymal origin, such as cartilage, bone, ligaments, nerve, muscle, blood vessels, etc.
Two new developments in taking stem cell approach for therapeutic purpose may have significant impact in future use of this technology. In one a trial to cure a devastating genetic defect by delivering stem cells to the womb is about to begin. The results from this study would have tremendous implication in other forms of stem cell therapy (http://timesofindia.indiatimes.com/home/science/First-in-womb-stem-cell-trial-next-year/articleshow/49330820.cms). One of the first approvals for marketing a stem cell product in Europe has recently been secured by a Nobel laureate-led company in Wales. This fast approval is related to curing heart failure. The European Medicines Agency (EMA) is keen to test such conditional approval procedures as part of a drive to evaluate promising life-saving treatments more swiftly than in the past (http://celltherapyltd.com/heartcel.html).
Stem cells from patients could be used to create diseased tissues (brain, muscles etc) for testing out new therapies in lieu of animal models. These are considered to be much better in mimicking patient response compared to cell-based and animal models for preclinical studies. Scientists from Brigham and Women’s hospital, Boston have created muscle fibers from stem cells derived from DMD mouse model that behaved like diseased muscles (http://insights.bio/cell-and-gene-therapy-insights/2015/08/05/stem-cell-derived-muscle-fibers-offer-scientists-new-avenue-for-muscular-dystrophy-treatment/). A minibrain created from stem cells of a patient suffering from a genetic disorder has helped in identification of a potential therapy for the devastating disease (http://www.ibtimes.com/mini-brain-derived-stem-cells-offers-potential-treatment-rare-disorder-2094881). These examples clearly show that patient derived stem cells can be transformed into relevant tissues and these tissues can be used to identify possible therapies and possible mechanism of the disease.
A common observation in GNE Myopathy is that the severity and age of onset vary, even among siblings. Many patients of Persian Jewish ancestry are able to walk for 15–20 years after the onset of disease while Japanese patients, on an average, need to use wheelchair within 10 years. It has been suggested that patients with a homozygous kinase mutation do better than those with compound heterozygous mutation. 147 different mutations in GNE have been identified so far in GNE Myopathy patients. A future area of research would be to find associations, if any, between type of mutation and disease presentation. It is possible that other genes may influence the overall outcome of disease manifestation. These could be studied in human patient cohorts, and in mouse model. The role of environmental factors, nutrition and lifestyle also need to be understood.