Cellular aging appears to be related to and perhaps caused by diminished DNA repair. To elucidate direct correlations between DNA repair capacity and senescence various parameters of cellular aging and DNA repair are studied simultaneously. Of special interest to us are features of DNA repair and senescence in cultured cells derived either from healthy or elderly probands as well as from patients suffering from premature senescence syndromes including Werner syndrome, Cockayne syndrome, dyskeratosis congenita and Down syndrome. We, and others, have seen the striking parallelism between reduced maximal lifespan, elevated levels of spontaneous chromosomal breaks, higher incidence of formation of micronuclei, a significant prolongation of cell cycle duration and above all, a diminished level of telomerase activity. Since DNA stability and telomere length are crucial in aging, some forms of cancer and senescence syndromes, we are developing new biomoléculas able to increase telomerase activity in patients. So far, in vitro and in vivo results have been so promising that we are already working on developing the first drug able to increase telomerase function in sick human cells. We think in the worst case our molecules will be able to stop cell degeneration in these patients, and perhaps induce some degree of reversion in them. This means that, if diagnoses at early stages, we might be able to provide patients with a normal lifespan.
There have been many studies demonstrating correlations between telomere shortening and proliferative failure of human cells. With each cell division, telomeres shorten by 50–200 bp, primarily because the lagging strand of DNA synthesis is unable to replicate the extreme 3′ end of the chromosome (known as the end replication problem). When telomeres become sufficiently short, cells enter an irreversible growth arrest called cellular senescence. In most instances cells become senescent before they can accumulate enough mutations to become cancerous, thus the growth arrest induced by short telomeres may be a potent anti-cancer mechanism. We are investigating ways to induce telomere shortening in rapidly dividing cells, such as cancer cells. Also, since some particular forms of cancers are triggered by DNA instability, which is triggered by shorting of telomeres, we are also studying the inverse approach in these cases: to increase telomerase activity so chromosomes become stable and these forms of cancer prevented.
Development of a new drug is of no use if it cannot reach the target cell in a precise and effective way. Nanotechnology has been a revolution in many fields, including biomedicine. We are developing new nanoparticles able to deliver our drugs to precise cells, differentiating sick cells from healthy ones by recognizing membrane markets. We can nanodeliver both DNA and protein in an efficient way. We use different nanopolymers, which allows us to control the time rate of release, ensuring a sustainable treatment in the future. Moreover, many of our nanovehicles can go through the brain barrier, so we might be able to treat some brain tumors in the next future, unreachable to physicians today. Finally, we can both encapsulate our molecules or attach them to the surface of our nanodevices, so we could target receptors and other cell membrane molecules and markers.
Since any treatment of a genetic disease needs to be based on an accurate and early diagnostic, this is a very important area for us. We develop new tests to diagnose rare diseases by sequencing one or a few of the patient’s genes, and some kits able to diagnose without any sequencing, just detecting the presence/absence of some biomolecules. Since this technology is quite limited, because sequencing is slow and only very few genes can be sequenced in parallel, we are extremely interested in massive sequencing techniques. Moreover, our interest is in sequencing of any patient WHOLE GENOME in a fast and cheap way. Currently, sequencing a whole human genome costs a minimum of $ 50,000 and generating usable results may take several months. We have teamed with private and public institutions to generate sequencing technology able to generate results under $ 5,000 and in a week tops. Also, these techniques will allow us to sequence up to 100 genomes per week in our labs. This means that we could diagnose ANY genetic disease or predisposition to suffer one to any patient. The first commercial prototypes will be available by 2,015.
Telomerase low activity is at the heart of aging. One of the side applications of our molecules is that since they are able to increase lifespan, their cosmetic applications are endless. Since they are peptides, their small size allows them to penetrate deep in the skin, rejuvenating it at unforeseen levels. Also, because they are of human origin, there are no reaction against them, no allergic results at all neither. Our peptides, encapsulated in our nanodevices, are simply the best combination as antiaging treatment.
Fragile X syndrome is the most common form of inherited mental retardation in males and is also a significant cause of mental retardation in females. It affects about 1 in 3,000 males and 1 in 4,000 females. Nearly all cases of fragile X syndrome are caused by an alteration (mutation) in the FMR1 gene where a DNA segment, known as the CGG triplet repeat, is expanded. Normally, this DNA segment is repeated from 5 to about 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment inactivates (silences) the FMR1 gene, which prevents the gene from producing a protein called fragile X mental retardation protein. Loss of this protein leads to the signs and symptoms of fragile X syndrome. Both boys and girls can be affected, but because boys have only one X chromosome, a single fragile X is likely to affect them more severely.
Oxidative stress is a strong problem in these patients. Our drug X-Tocomir has already passed Clinical Phase III against a placebo control group. Treated patients show a very clear improvement in their cognitive, learning and behavioral capacities. We plan to bring this drug to patients by the end of 2015.
IDIOPATHIC PULMONARY FIBROSIS
IPF is a serious and debilitating disease where the alveoli (the tiny air sacs of the lungs) and the lung tissue next to the alveoli become damaged and scarred. It is typically suffered at ages after 60 but sometimes a particular aggressive version appears in patients in their early 30’s. The disease is mortal in most cases after the 3rd year of being diagnosed. The main symptom is shortness of breath that gradually gets worse. The exact cause is not known. Treatments include steroids, and other medicines, and increasingly lung transplantation may be offered. The exact cause is not known (hence the term idiopathic). It was thought that inflammation within the alveoli played a big role in the development of idiopathic pulmonary fibrosis and that this inflammation led to scarring and fibrosis. This led to the name cryptogenic fibrosing alveolitis. However, treatments that help to reduce inflammation are not always effective. Therefore, the role of inflammation has recently been brought into question.
The current thinking is that somehow the cells that line the alveoli are damaged in some way. The cells then try to heal themselves. But, this healing process becomes out of control, causing thickening and damage to the walls of the alveoli, and fibrosis (scarring) of the alveoli and lung tissue. The thickening and scarring reduces the amount of oxygen that can pass into the blood vessels from affected alveoli. Therefore, as the disease progresses, less oxygen than normal is passed into the body when you breathe.
IPF is rare. Fewer than 3 in 10,000 people develop this disease. However, it seems to be getting more common. It can affect anybody at any age but it most commonly develops between the ages of 50 and 70. It seems to be more common in men than in women. At present there is no cure for idiopathic pulmonary fibrosis and the optimal treatment has not yet been found. Only two drugs are in the market and they have shown very strong adverse effects and they are not efficient in all patients, also, they don’t prevent the disease from appearing and they are of little or no use in an advanced state of IPF.
Our drug candidate, Neumomir, has shown very clear potential in animal models suffering the disease, both as preventive and therapeutic use and also for well advanced stages of the disease. It will enter clinical trials in 2016.
Muscular dystrophies (MD) are a group of inherited genetic conditions that gradually cause the muscles to weaken. This leads to an increasing level of disability. MD is a progressive disease, which means that it gets worse over time. It often begins by affecting a particular group of muscles before affecting the muscles more widely. Some types of MD eventually affect the heart or the muscles used for breathing, at which point the condition becomes life threatening. Prevalence is typically between 1 in each 4,000 o 5,000 people.
There is no cure for MD, but treatment can help manage many of the symptoms. MD is caused by changes (mutations) in the genes responsible for the structure and functioning of a person’s muscles. These mutations cause changes in the muscle fibers that interfere with the muscles’ ability to function. Over time, this causes increasing disability.
Some of the more common types of MD include:
• Duchenne muscular dystrophy – one of the most common and severe forms, it usually affects boys in early childhood; men with the condition will usually only live into their 20s or 30s
• Myotonic dystrophy – a type of MD that can develop at any age; life expectancy is not always affected, but people with a severe form of it may have shortened lives
• Facioscapulohumeral muscular dystrophy – a type of MD that can develop in childhood or adulthood, it progresses slowly and is not usually life threatening
• Becker muscular dystrophy – closely related to Duchenne MD, but it develops later in childhood and is less severe; life expectancy is not usually affected so much
• Limb-girdle muscular dystrophy – a group of conditions that usually develop in late childhood or early adulthood; some variants can progress quickly and be life threatening, whereas others only develop slowly
• Oculopharyngeal muscular dystrophy – a type of MD that usually doesn’t develop until a person is 50-60 years old and doesn’t tend to affect life expectancy
• Emery-Dreifuss muscular dystrophy – a type of MD that develops in childhood or early adulthood; most people with this condition will live until at least middle age
We are developing a drug against Duchenne, preventing the muscle fiber to become fibrotic and lose its function.
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