Chapter Five
The End of Hereditary Rare Disease
When I was a family doctor back in England in the 80s and 90s, I had at least one patient with a rare disease on my list of three thousand patients. Anthony Michaels lived with his devoted mother in a small, modern, two-bedroom house on the other side of town. Anthony had cystic fibrosis. In those days he had a life expectancy of only sixteen years.
Anthony was in and out of the big regional hospital in Birmingham (England’s second biggest city) every few weeks, and indeed he had a schedule of admissions prearranged so that he could receive intense courses of intravenous antibiotics and physical therapy to help clear the sticky plugs of mucus blocking his airways that is characteristic of cystic fibrosis.
Despite these regular admissions, Anthony would frequently succumb to some new chest infection, his breathing would deteriorate, his cough would get worse, and his temperature would climb. He would be rushed into the hospital for emergency courses of his usual treatment of powerful intravenous antibiotics and to be put on a breathing machine.
When I would see him a few weeks later, he would look emaciated but both he and his mum would be joking and playfully teasing me, despite the knowledge that as a teenager, he was now only expected to live another year or two.
One day, I was asked by the specialist pediatric pulmonologist at the big regional center, who looked after about thirty children with CF, whether I would give Anthony “home intravenous antibiotic therapy.” What that meant was that I (or one of the competent and experienced district nurses) would have to go into the Michaels’ home, put an intravenous line with a powerful antibiotic (gentamicin, if my memory is correct) into one of Anthony’s fragile veins, and after a period of observation to ensure all was well, remove the IV access and tidy up.
In those days, there were no inhaled antibiotics and although Anthony daily took many capsules of the vital pancreatic enzyme supplements that he required, there was no effective treatment to keep the lungs clear of the nasty bacteria, especially Pseudomonas aeruginosa, which he therefore harbored in low levels even on the best of days. On bad days, the number of these nasty bugs would surge and down he would go with the next chest infection. Inevitably, a day would come when the bacteria would become resistant to the lifesaving, high doses of gentamicin he received.
I agreed to provide “domiciliary IV antibiotic care” for Anthony, although it had not been “approved” or become standard practice at that time. Already the expensive drugs I prescribed to keep Anthony alive had attracted some concern from the local healthcare administrators and few other GPs within the West Midlands region, covering a large part of central England, had agreed to give IV antibiotics to their CF patients at home, preferring them to journey in to the regional center for their regular weekly course.
Over the years, Anthony had a series of setbacks, and he had several operations for squints, unrelated to his breathing and digestive problems. I left my practice, but my guess is that he would surely have been one of those to receive the life enhancing cycling inhaled tobramycin antibiotic (TOBI, a cousin of gentamicin) by nebulizer, which contributed to life expectancy doubling to 32 years. He would probably have been eventually listed for a lung or double lung or even a heart-lung transplant.
For several years, I worked as a drug development physician at Chiron Corporation (acquired by Novartis in 2005), which was working with TOBI for CF and another pulmonary disease, bronchiectasis. Chiron then moved on to work on a project using a drug to prevent lung transplant rejection. The memory of Anthony’s cheeky grin and bubbly sense of humor always reminded me of what physicians in the pharmaceutical industry are trying to achieve: the development of drugs that will add years of good quality life to people like Anthony.
I believe that Anthony did indeed receive a heart-lung transplant, but that he did not long survive that procedure.
Anthony was one of the patients whose humor and fortitude in the face of adversity, and with little hope of living a normal life span or quality of life, inspired me as a doctor. At least a firm diagnosis had been made and although there was then no definitive treatment, his mother and he were told what to expect.
I had other patients who had no diagnosis at all. They had strange conditions and were repeatedly examined by top specialists who agreed something was amiss, but couldn’t tell what it was. In this new era of genomics, many of these rare diseases, alas most still lacking any effective treatment, can at least be accurately diagnosed and the specific genetic mutation identified. And many more of these rare diseases will soon no doubt be revealed.
Currently about seven thousand rare diseases have been characterized and the faulty gene isolated. There are estimated to be at least another seven thousand which have not yet had a causative genetic mutation identified, and thus are untreatable, but gradually these diseases will be understood.
Most of these rare genetic disorders are only diagnosed once the patient has developed symptoms of the disorder, bringing him or her to the attention of doctors. And because these diseases are due to faulty genes, the child is destined to develop the disease from the moment they are conceived, literally, when the father’s sperm meets the mother’s egg.
These genetic diseases are unlikely ever to be fully preventable, although many can be screened for in early pregnancy, with the option for the parents to end the pregnancy of an affected embryo. The next step for those babies is to develop effective treatments for these rare and often lethal diseases.
I believe that oligomers may be a potential answer for many of these.
I, too, am a parent affected by a rare disease. Multicystic dysplastic kidney (MCDK) is a rare disease occurring in one in roughly 4,300 births. Babies born with one dysplastic kidney can survive well on the remaining normal kidney. Ten weeks before he was born, one of my own sons was detected with this rare defect. Unfortunately, he appeared to have a blockage affecting his other kidney, meaning neither of his kidneys would work. Within hours of his birth he was subject to an operation to try and bypass his blocked kidney, but alas the operation failed. He was brought from the operating theater to me and I was given the news that he was expected to die within the next twenty-four hours. I was left to cuddle this little bundle in a hospital cubicle, miles away from where his mother was recovering from giving birth to him. Against the odds, he survived the day, the night and then the next day. After several operations to re-plumb his solitary, working, but now damaged kidney and then remove his non-functioning one, he survived childhood with blood pressure treatment, treatment for the side effects of that treatment and various supplements. So, yes, I know from personal experience how rare disease can affect a family.
There is no single, widely accepted definition for rare diseases. Some definitions rely solely on the number of people living with a disease. Other definitions include other factors, such as the lack of adequate treatment; the severity of the disease; or a lack of resources to care for the patient. Some people prefer the term orphan disease and use it as a synonym for rare disease, such as the European Organization for Rare Diseases (EURORDIS) which combines both rare diseases and neglected diseases (those with no treatment available) into a larger category of “orphan diseases.”
The orphan drug movement began in the U.S. over thirty years ago. It was the moving force behind the Orphan Drug Act (ODA) of 1983, a federal law designed to encourage research into rare diseases and possible cures. The ODA includes both rare diseases and any nonrare diseases “for which there is no reasonable expectation that the cost of developing and making a drug available in the U.S. for such disease or condition will [be] recovered from its sales in the U.S.” as orphan diseases. Since 1983, more than 2,200 drugs have entered the research pipeline and more than 360 have completed their development and been approved for marketing. Currently orphan products account for about one third of all New Molecular Entities being approved.
The subsequent Rare Disease Act of 2002 defines rare disease strictly according to prevalence, specifically “any disease or condition that affects less than 200,000 persons in the United States,” or about one in 1,500 people. Prevalence is defined as the total number of cases of the disease in the population at a given time, or the total number of cases in the population divided by the number of individuals in the population. It is used as an estimate of how common a disease is within a population at a certain point in time. This should not be confused with incidence (the number of new diagnoses in a given year), which is used to describe the impact of rare diseases.
The increased regulatory attention afforded to rare diseases led to the U.S. Food and Drug Administration (FDA)’s Center for Drug Evaluation and Research (CDER) establishing a Rare Disease Program in February 2010, with its own Associate Director of Rare Diseases (ADRD) reporting to the Director of the Office of New Drugs (OND). This new team was given the goal of facilitating and supporting the research, development, regulation and approval of drugs for the treatment of rare disorders, and was to complement the work of FDA’s Office of Orphan Product Development (OOPD). It would become the focal point of contact at FDA for Rare Disease stakeholders, such as companies developing small molecule drugs, oligomers and biologics and patient advocacy organizations. The rare disease program team would facilitate interactions with CDER and their sister Center of Biologic Evaluation and Research (CBER). The ADRD would help drug development companies navigate complex regulatory requirements and the increasingly intricate bureaucracy that is the FDA. There is still much to do. Currently, only about two hundred of the seven thousand characterized rare diseases in the U.S. have an approved treatment available.
I have worked on several rare disease programs during my twenty years as a physician in the pharmaceutical industry, and led numerous interactions with regulators in the U.S. (FDA) and Europe (European Medicines Agency or EMA). I am pleased that in some cases the new drug applications that I worked on have already been submitted and approved. I suspect that the increased FDA focus on rare diseases will indeed lead to faster development programs and more approval for ground-breaking pharmaceutical products, and hopefully oligomers, in the years ahead.
The key to understanding FDA structure, roles and responsibility as it pertains to rare disease is to understand the complementary but distinct separation between the Office of Orphan Medicinal Products (OOPD) and the Office of New Drugs (OND)’s Rare Disease Program (RDP), which can be summarized this way (Figure 5.1):
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| Common areas: coordinate communication across FDA centers and offices, and with outside stakeholders; enhance rare disease information available on FDA website | |||
* ODA =Orphan Drug Act. IND =Investigational New Drug (the application to the FDA to allow initial human testing). NDA = New Drug Application (the enormous dossier containing all the research, animal testing, clinical studies, manufacturing and quality testing that the FDA reviews prior to approving the product suitable for marketing). BLA = Biologic License Application (the NDA for biologic products).
Figure 5.1. The similarities and differences between the FDA’s Office of Orphan Medicinal Products (OOPD) and the Office of New Drug’s Rare Disease Program (OND RDP)
Further evidence of the increasing FDA interest in rare diseases is provided by the seven rare disease approvals (three drugs and four biologics) in the first nine months of 2010 (Appendix B) of a total of 17 New Molecular Entities (NMEs) approved (ten drugs as NDAs and seven biologics as BLAs).
In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about one in 2,500 people. The European definition of a rare disease is a life-threatening or chronically debilitating disease that is of such low prevalence that special combined efforts are needed to address it. The term “low prevalence” is later defined as generally meaning fewer than one in 2,000 people, consistent with the European Commission’s definition of rare. Diseases that are statistically rare, but not also life-threatening, chronically debilitating, or inadequately treated, are excluded from their definition. The definitions used in the medical literature and by national health plans are similarly divided, with definitions ranging from one in a thousand to one in two hundred thousand. The Global Genes Project estimates there are some 350 million people worldwide currently affected with a rare disease.
Although each individual rare disease is rare by definition, the sheer number of different, individual rare diseases results in approximately eight percent of the population of the European Union being affected by a rare disease, close to the estimated ten percent of U.S. patients who are similarly suspected of suffering from a rare disorder. Most rare diseases are genetic, and thus are present throughout the person’s entire life, even if symptoms do not immediately appear. However, many rare diseases appear early in life, and about thirty percent of children with rare diseases will die before reaching their fifth birthday. Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis (CF), a genetic disease, which is relatively common in Caucasian Europeans. The recessive gene is carried by approximately one in 25 people. For the disease to occur both copies of the gene must be affected. Thus 1/25 x 1/25 partnerships are likely to result in two carriers coming together (i.e. one in 625 partnerships). These parents have a one in four chance that their child will receive the recessive gene from both partners. This gives an incidence of one in 4 x 625 new births = one in 2,500. In Asians, CF is even rarer.
Finland has a higher prevalence of about forty rare diseases; these are known collectively as the Finnish disease heritage. Ashkenazi Jews also have a higher prevalence of certain rare diseases with an estimated one in four individuals being a carrier of one of several genetic conditions, including Tay-Sachs Disease, Canavan, Niemann-Pick, Gaucher, Familial Dysautonomia, Bloom Syndrome, Fanconi anemia and Mucolipidosis IV.
There are many companies whose development programs now focus on rare or orphan diseases including Synageva BioPharma Corp. (based in Massachusetts), Swedish Orphan Biovitrum, Shire plc (British), Genzyme (also based in Massachusetts but recently acquired by the French giant, Sanofi Aventis), Lundbeck (a Danish company) and BioMarin (a small California based company). Disappointing as it is that there has not been more work conducted on rare diseases in the past, it is encouraging to learn how much research is now underway. Perhaps discoveries in rare diseases will have much greater impact to future healthcare than is expected.
Take the example of progeria. Progeria is a very rare disease affecting about one in four million people. It is now known to be caused by a single base change from a C to a T in the middle of the Lamin A gene (LMNA). This causes 150 nucleotides in exon eleven to be spliced out of the final mRNA, and the resulting abnormal protein lacks fifty amino acids. The disease, also known by its longer title of Hutchinson-Gilford progeria syndrome (HGPS), results in rapid aging (at about seven times the normal rate) and children dying usually around age 12 to13 years from a heart attack, by which time they look like they are in their eighties.
The molecular biology behind progeria was characterized some years ago, with a buildup of a toxic protein (progerin) in the cells that led to the premature heart disease. In an experimental mouse model, the toxic protein could be reduced by treatment with a farnesyl transferase inhibitor (FTI) drug (lonafarnib), and the mice survived without the premature cardiovascular disease.
Since 2007, a clinical trial has been underway in progeria to see if the same drug will also work in the human disease, although the ClinicalTrial. Gov website for this study (run by Schering-Plough and the Progeria Research Foundation at Boston Children’s hospital) has not been updated since December 2007. At that time, the study was slated to complete in October 2009. There are only 42 identified children in the world (from at least 15 countries – including Pakistan, Croatia, Korea, Argentina and Venezuela) with this rare condition making the conduct of this clinical study incredibly challenging. Having been in touch with the Progeria Research Foundation in mid 2012, I understand that the results from this study will be publically released soon. I hope they are positive.
In addition, it has been found that the toxic protein does build up in the cells of the elderly, so perhaps a better understanding of the rare disease progeria will have future important implications for aging in general. Maybe in time, it will be possible to skip the point mutation in the precursor mRNA with an oligomer and create a different mRNA that will be much closer to the normal message, with most of the 150 missing nucleotides restored. This could conceivably prevent the buildup of the abnormal progerin and the devastating disease progeria.
William Harvey was best known for determining how the circulatory system worked, but in 1657 he remarked in a letter about rare diseases: “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings beside the beaten path; nor is there any better way to advance the proper practice of medicine that to give our minds to the discovery of the usual law of Nature by careful investigation of cases of rare forms of diseases. For it has been found in almost all things, that what they contain of useful or applicable nature is hardly perceived unless we are deprived of them, or they become deranged in some way.”
Many infectious diseases are prevalent in a given geographic area but rare everywhere else, usually limited by the distribution of specific climatic conditions or certain animals required for their life cycle, or both. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare. The classification of other conditions depends in part on the population being studied: All forms of cancer in children are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common. With a single diagnosed patient only, ribose-5-phosphate isomerase deficiency is presently considered the rarest genetic disease. The distribution of disease areas that were targeted for an orphan product in development, according to the FDA, is provided in Figure 5.2.
Figure 5.2. Disease categories targeted by Designated Orphan Drugs as a percentage of total (FDA data 2000 - 2006).
When I was a practicing family doctor, every year there would be a small number of cases amongst my 3,000 patients who either suffered some strange disease, or who joined my list with some pre-existing, but undiagnosed condition. In retrospect, I wonder how many of those often puzzling and frustrating cases (for the patient, their family and me) would now be diagnosable with modern gene sequencing technology.
NORD
In the decade before 1983, only ten new drugs were developed by industry for rare diseases. Since they affected no more than 200,000 Americans, they were receiving little attention. Research dollars and expertise were focused on the development of blockbuster drugs (see Chapter 1) for common diseases that were more likely to repay the huge costs of developing them. In 2010, it was estimated from publicly available data, that the cost to develop a new drug would exceed an astonishing one billion dollars.
Back in the early 1980s, leaders of rare disease patient advocacy organizations recognized that there were certain problems their patients with any rare disease and their families shared. It was clear that, while each disease may be rare, together these diseases affect millions of Americans, an estimated one in ten (probably thirty million patients). As a result, they collectively campaigned, calling for national legislation to encourage the development of treatments for rare diseases. The result was the 1983 ODA, and the patient advocacy leaders who had brought national recognition to the problem founded the National Organization for Rare Disorders (NORD) as an umbrella organization to represent the rare disease community.
NORD, a charitable organization, is a unique federation of over 130 voluntary health organizations that is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and service.
In theory, many rare genetically determined diseases that have previously been untreatable may now be amenable to one or more of the oligomers either in clinical development or in early preclinical development – or even in still earlier research.
There are numerous examples of oligomers already now in the clinical phase of their development for rare disease, i.e. they are now being tested in humans. The diseases for which they are targeted are provided in Figure 5.3. An update on these various programs and many other more common disease programs was provided by the sponsoring companies at a U.S. meeting hosted by the FDA and the Drug Information Association in April 2012.
* as of October 2012, Alnylam has partnered with Genzyme to develop this drug for Japanese and Asia-Pacific markets.
Figure 5.3 Oligomers currently in clinical development for rare disease indications
The companies developing new drugs for rare diseases benefit from the advocacy and various services NORD (and its European and Canadian counterparts) provides aimed at complementing them:
• Information about diseases and referrals to patient organizations (through their website at: http://www.rarediseases.org/rare-disease-information/rare-diseases)
• Patient assistance programs: Since 1987, NORD has helped patients receive drugs that could save or sustain their life. They also help with the cost of insurance, co-payment fees, diagnostic tests and even travel expenses so patients can see doctors who specialize in a particular rare disease.
• Research grants and fellowships
• Advocacy on public policy issues
• Help in forming organizations and mentoring for patient advocacy groups
NORD in July 2011 had information about 15 clinical studies on its website, for such diverse rare conditions as: Craniosynostosis (in California), Ehlers-Danlos Syndrome Type IV (EDS type IV) (in Washington), Hirschsprung Disease (at Johns Hopkins University) and Wegener’s Granulomatosis (in Toronto, Canada). In addition, NORD produces regular newsletters for patients and their families and continues to stimulate congressional focus on addressing these previously underserved voters.
Whether due to the efforts of NORD or not, the general public has become more aware of these rare diseases.
EURORDIS
EURORDIS can be considered as the European equivalent of NORD, as a non-governmental patient-driven alliance representing more than 479 rare disease patient organizations in over 45 European countries, which was conceived for similar reasons. Founded in 1997, it is now administered by 26 staff based in Paris and Brussels. At the end of August 2010, EURORDIS settled into newly renovated dwellings in the grounds of the Hospital Broussais, Paris with their partners in the Plateforme Maladies Rares (Rare Diseases Platform) created in 2001. EURORDIS presents patient stories for 15 rare diseases (Alkaptonuria; Angelman syndrome; Chromosome 18 syndrome; Fragile X syndrome; Hereditary spastic paraplegia; Lysosomal disorders; Marfan syndrome; Marshall-Smith syndrome; Niemann-Pick; Osteogenesis imperfecta; Progeria; Retinitis pigmentosa; Spina bifida; Stiff man syndrome and Strumpell-Lorrain) on their website: http://www.eurordis.org/living-with-a-rare-disease.
EURORDIS has campaigned vigorously in Europe and claims to have made considerable progress. From their website (www.eurordis.org):
EURORDIS assisted development and adoption of the EU regulation on Orphan Medicinal Products in 1999.
EURORDIS participates in the Committee for Orphan Medicinal Products (COMP) at the EMA with two full members and one observer in the COMP. It thus plays an important role in the orphan drug development process in Europe.
EURORDIS campaigned for incentives in the development of orphan drugs:
Fee waiver for orphan designation.
Reduced fees for Marketing Authorization Applications (the European equivalent for NDA), inspections, variations and protocol assistance.
Two year extension of market exclusivity for orphan pediatric drugs.
EURORDIS currently advocates for:
Parallel E.U.-U.S. submission and designation of orphan drugs to speed up development and access to new drugs based on a single regulatory submission.
Creation of a Clinical Research Program for orphan drugs in support of designated products.
National incentives such as research grants and tax credits.
EURORDIS collaborates closely with the EMA for the production of quality information on orphan drugs for patients:
At the time of orphan drug designation, EURORDIS reviews all Public Summaries of COMP opinion and liaises with concerned patient groups.
At the time of marketing authorization, EURORDIS facilitates the reviewing of EPARs (European Public Assessment Reports) by patients with rare diseases.
EURORDIS identifies and supports patient representatives to participate in:
Protocol development assistance.
Meetings of the scientific advice working party.
Other meetings e.g. discussions on guidelines and risk management programs.
EURORDIS has assisted over sixty rare disease patients provide input to the various orphan drug development process activities.
EURORDIS advocates for patient access to authorized orphan drugs
Regular surveys to assess and compare orphan drugs availability.
Promotes European common policy and criteria for orphan drug access.
EURORDIS Orphan Drug Task Force providing regular information updates to a network of volunteers affected by rare diseases:
Two million EU citizens potentially benefitting from these drugs.
560 orphan drugs designated since 2000.
52 orphan drugs with marketing authorization in EU since 2000.
CORD
The Canadian Organization for Rare Disorders (CORD) is the national network of organizations that represents people affected by rare disorders within Canada. CORD’s intention is to provide a strong common voice advocating for a healthcare system and health policy for those with rare disorders. Other countries are following the examples of the U.S., Canada and Europe and are also considering methods for encouraging development of orphan products, but with increasing harmonization, especially pertinent for orphan drugs, most national regulatory authorities tend to follow the lead of the FDA, EMA and PMDA.
In February 2008, the first Rare Disease Day was held in both Canada and Europe. The idea behind this holiday is to focus more attention on rare diseases. It has spread to the U. S. and takes place on February 28th each year, except leap years where it is observed on the 29th.
As a family doctor, I have served families who have had to deal with the diagnosis and management of a rare disease in their midst, and have had the experience myself. It is a life-changing experience. I am confident that the pharmaceutical industry is now on the road, with oligomers, to develop many novel drugs that will make enormous differences to the lives of patients afflicted with one of several rare diseases in the imminent future. If all goes well, as I think it will, the early oligomer approvals should herald the dawn of a new age in how medicines are discovered, designed and developed and we will truly see personalized medicine become a 21st century reality, and at last some hope for those 350 million people worldwide who suffer from a “rare” disease. So how do these oligomers treat rare disease? And do they cure the patients?
The answer to the second question is sadly, no. In the case of genetically determined disease, such as Duchenne muscular dystrophy (DMD), if your son has the genetic mutation it will be present throughout his life. However, by camouflaging that mutation using a very precisely targeted oligomer to bind to a short section of the pre-mRNA as it enters the nuclear spliceosome, it may be possible to splice out a mutant exon and splice together normal exons. Or the reading frame could be restored to allow a shorter but functional strand of mRNA to produce a shorter but functioning protein. In the case of DMD, that protein is dystrophin. Any splice switching or splice modulating oligomer will need to be taken for the rest of the patient’s life to ensure that the same molecular gymnastics continue to occur for a happier and healthier future.
DMD is an example of how much more complex the story really is. Remember that there are 79 exons in the dystrophin gene. Any one of these, or more than one, may be missing or contain a mutation. Over the last thirty or so years, most boys with DMD are tested at diagnosis and the exact number and location of missing or mutated exons is determined. The data has been stored anonymously on a worldwide register. Doctors who diagnose a DMD child are encouraged to add details of every new case.
Leiden University in the Netherlands is where this database of genetic mutations for DMD is stored and overseen – and by 2006 over 4,600 different mutations of the dystrophin gene had been reported. Most of these led to either the severe DMD (if no dystrophin was produced as a result of the mutation), or the much milder Becker muscular dystrophy (BMD) if a shortened version of dystrophin was produced. In the latter situation, the mRNA might miss one or more exons but the sequence of three letter words was otherwise preserved and the mutation was said to be “in frame,” allowing the ribosome to read the mature mRNA.
The difference between in frame and out of frame deletions can be explained using a sentence that I previously used, made up of three letter words to represent codons:
the big red fox ran far and saw the dog and cat hit the man
An example of an out of frame deletion is where the last nucleotide from the second codon, the g of big is missing. After splicing the pre-mRNA exons together to form the mature mRNA, the message would read like this:
the bir edf oxr anf ara nds awt hed oga ndc ath itt hem an
The ribosome would make no sense of this. Or maybe it might lead to the generation of an unwanted disease-causing protein. In the case of a boy with DMD, the vital dystrophin protein would be missing from the muscle cells. In the case of BMD, a whole codon or even several complete codons could be missing, for instance: “ran far and” but the remaining words in the message would still be intelligible. Although the sentence is short, and hence the sequence of amino acids in the finished dystrophin would be shorter than normal, the sentence still makes sense and the generated protein still works.
This is how a BMD in frame deletion mRNA message might read, using the above example:
the big red fox saw the dog and cat hit the man
BMD patients may lead a completely normal active life and never even be diagnosed. Often, a diagnosis only occurs when they are being investigated for something else entirely.
The Leiden database stores the exact sequence, when it is known, for the many possible mutations, and allows researchers to determine which extra exon needs to be skipped, and in how many people, to potentially convert an out of frame mutation back into frame. In so doing, the idea is to convert the lethal DMD disease into a milder BMD. That hypothesis is now being actively tested in clinical studies in the U.S. and Europe, with encouraging preliminary results.
The database compares the sequence of codons for the same gene in different species – for instance it lists 46 vertebrates that have been so sequenced. This helps to know if the human disease has animal equivalents to test the oligomers on before going in to human studies. Three breeds of dogs – Labradors, Beagles and King Charles Spaniels have been discovered to have the canine equivalent of DMD. These unfortunate animals may help us with the development of oligomers for the human disease. In the case of the spaniels, the disease is very similar to the human one. It is lethal and only seen in male dogs. It is also genetically similar to the human disease and may be corrected by skipping exon 51 (of the 79 canine dystrophin exons). Skipping this exon to restore the reading frame is also the most common target in humans. The disease in beagles is due to a different mutation, still in the dystrophin gene, but in a different place. Beagles require a cocktail of three oligomers to overcome the mutation and restore the reading frame.
Scientists in Japan tested the three oligomer cocktail on some dystrophic beagles and the results, in comparison to an untreated littermate, even after only five weeks of therapy, were most encouraging.
These results can be seen in a pair of video clips on YouTube:
Untreated dog:
http://www.youtube.com/watch?v=lRzBc3kvhKM
Treated littermate:
http://www.youtube.com/watch?v=14VcMtpympI
Those of us who have worked in DMD, or in any of the other lethal rare diseases, always hope that this promising outcome can be replicated in humans and that the oligomer can be quickly made available.
However, there are many more steps that a new drug has to go through before that can happen. Two companies are already collaborating in large scale clinical studies testing the effectiveness and safety of their exon 51 skipping oligomer: the Dutch company Prosensa and the British pharmaceutical giant, GlaxoSmithKline. Not far behind is the U.S.’s Sarepta Therapeutics (formerly AVI BioPharma), with a different chemical class of oligomer. It’s going through a longer, second study in DMD boys at a higher dose than was previously studied in the UK. In October 2012 Sarepta announced clinical benefits had been observed at 48 weeks in their study, and by December another announcement reported continued benefit seen at 62 weeks of dosing. There are high hopes that one or both programs will ultimately succeed and start to turn the tide on this dreadful disease.
When that day comes, it is very likely that more investment will flood into companies with promising oligomer candidates for other rare diseases. As the regulatory path for these promising treatments become familiar, the development of many other therapeutic oligomers becomes more feasible.
Of course, rare disease is only one area of the many potential uses of these oligomer-based drugs. Next I’ll show you how they can destroy contagions and put an end to the spread of plague-like viruses.
Summary
Rare diseases affect one in every ten people worldwide. As the understanding of the human genome evolves, many more of the uncharacterized orphan diseases will become better understood and the exact genetic mutation leading to them documented. The opportunity to develop nucleic acid-based oligomers to treat these rare genetic mutations may become available. For some of these, research is now well underway; in a few examples, it has already entered the long awaited clinical studies. Hence the splice switching or translation suppressing oligomers may become real therapeutic options within the next few years.