BioPharma Needs A Safe, Reliable Way To Repair Broken Genes

4/11/12

The sequencing of the human genome didn’t immediately lead to treatments for a number of diseases, as many had hoped and a smaller number had predicted. However, the enormous drop in the price of DNA sequencing over the past decade has now made it possible to sequence an individual’s complete genome for less than $5,000.

Uncovering the molecular underpinnings of human diseases is not a new endeavor, but the pace at which these discoveries are being made is breathtaking. It is now cost and time effective to use DNA sequencing as a diagnostic tool for individuals suffering from a wide variety of congenital maladies. Instead of putting patients through batteries of expensive and sometimes invasive testing, DNA sequencing is becoming the go-to method for discerning the molecular truth. Science journals are packed with articles in which sequencing has led to the identification of a growing number of genes that, when altered, appear to be the causative agents responsible for these diseases. Here is just a sampling of medical conditions that have been tied to specific genetic defects over just the past few years:

Ogden syndrome (NAA10), dominant X-linked juvenile and adult onset ALS and ALS dementia (UBQLN2), dopa responsive dystonia (SPR), early onset severe bowel inflammation (XIAP), craniosynstosis (HUWE1), developmental disorder (DDOST), Hadju-Cheney syndrome (NOTCH2), Proteus syndrome aka elephant man disease (AKT1), Thrombocytopenia-absent radius [TAR] syndrome (EBN8A), hereditary diffuse leukoencephalopathy with spheroids (CSF1R), ALS and frontotemporal dementia (C9ORF72), juvenile ALS (SIGMAR1), adenoid cystic carcinomas (MYB-NFIB), postlingual nonsyndromic hearing impairment (PRPS1), familial diarrhea syndrome (GUCY2C), and even a type of stuttering (NAGPA).

These discoveries build on the work of the past few decades, which saw the root cause for a number of diseases identified by other genetic approaches. These include cystic fibrosis (CFTR), Huntington’s disease (HTT), Tay Sachs (HEXA), Duchenne muscular dystrophy (DMD), and sickle cell anemia (HBB). Sequencing efforts may not directly help identify all of the components that contribute to multi-factorial illnesses like heart disease and diabetes, or chromosomal abnormalities like Turner or Klinefelter’s syndromes. However, the overall impact of this sequencing work has been spectacular, and we’re not done yet. The National Organization for Rare Disorders reports that there are 6,000-7,000 known rare diseases that affect some 25-30 million Americans. Approximately 250 of these diseases have FDA-approved therapies. The molecular pathology behind a much larger number of these diseases has still not been discovered. That leaves a lot of people looking for both an understanding of the causes of their specific diseases as well as treatments that don’t currently exist. Adding to our informational database: an effort is underway to sequence the genomes of 10,000 different vertebrate species by 2015.

During this same period of time when the genetic causes for a number of diseases have been identified, various methodologies have been developed and tested to try to treat these maladies. The three most prominent are gene therapy, antisense technologies, and RNA interference techniques. Numerous biotechnology companies were founded over the past 25 years to develop effective medical treatments using these methods. Despite the support of numerous investors and the efforts of many talented scientists, these techniques have mostly failed in the clinic, and many of the companies faded away. Happily, there have been a few small achievements in the past few years. Gene therapy clinical trials have been successfully deployed to treat a few patients with Leber’s congenital amaurosis (a rare congenital eye disease), two boys with adrenoleukodystrophy (subject of the film Lorenzo’s Oil), and 14 children suffering from several forms of severe combined immunodeficiency. Antisense technologies produced only one marketed treatment, Isis Pharmaceuticals’s fomivirsen, which was approved in 1998 for cytomegalovirus-induced retinitis in patients with AIDS. The product was later discontinued when the market shrank dramatically due to the introduction of more effective anti-retroviral therapies for these patients. I am not aware of any late-stage clinical successes achieved to date using RNAi methods, and a number of Big Pharma companies have, after an initial wave of enthusiasm, moved away from developing this technology.

The good news is that we are gaining a much greater understanding of the molecular causes for a wide spectrum of human diseases, as well as the associated biology. The bad news: knowing which genes are responsible for these maladies still leaves us a long way from fixing them. As the list of diseases that have an identifiable cause grows, so does the potential to alleviate the physical and emotional hardships that underlie them. Suppose we could repair such defects? The number of diseases that could be cured would be large, and the costs for society in dealing with these illnesses should be lessened. What we need is a major technological advance that allows for the correction of molecular genetic alterations at the individual level. How might this breakthrough be achieved? I see three possible paths forward:

1) PhRMA and BIO members combine forces and put together a major, focused attempt to figure out how to repair defective genes. Participating companies would pool their financial resources and launch a serious effort to leap over the technological hurdles. The industry dreadnoughts are all sitting on huge piles of cash; Amgen, Novartis, Roche, and GSK all had at least $8 billion in cash reserves back in 2008. Contributions could be tiered by the size and/or profitability of the companies that contribute the funds. Organizers can make some guesstimates about total costs and define a time period for funding, such as $300M over a five-year period. I would suggest that most of the efforts be launched out of a single physical hub, with only a smattering of participants linking in electronically. It’s the hallway conversations and the half-filled in white boards, along with the heated discussions over lunch, that will provide the sparks that ignite the flames. Companies that contribute an appropriate share of funds to the project would automatically be granted a license to any ensuing technologies.

Why would PhRMA and BIO members want to do this? Big Pharma companies are desperately searching for new ways of identifying innovative therapies. Many of them have reduced the size of their internal research programs in the face of declining productivity. Pfizer alone has cut the cost of their R&D efforts by some 25 percent over the past few years. A large number of pharma companies have set up their own internal venture capital investment groups, while others have turned to academia in search of new medicines. There are a large number of attractive genetic targets, as outlined above, that the companies can develop treatments for if the program is successful. One big obstacle: companies already working (or financially invested) in this space may not relish the thought of having to compete with this program, and would launch an effort to block it.

2) Put it in the hands of the U.S. Government. The government successfully ran the Manhattan and Human Genome Projects, so why shouldn’t they run this one? I can think of several reasons. Let’s start with an obvious one: where would the additional money come from to pay for this? The government has done an excellent job at constructing a framework of resources that help stoke the nation’s biological research engine, but let’s face it: the government is beyond broke. Pulling money out of other parts of the NIH machinery again (as was done with the creation of the new Translational Sciences program) should not be an option. Reducing the already (pathetically) low funding rate of NIH grants is a non-starter. Saying that the bureaucracy in Washington is a bit more convoluted now than in the 1940s or even 1990s would grossly understate the obvious. Political gridlock is so overwhelming that proposing the idea in Washington might be tantamount, mixed metaphorically speaking, to shooting the idea down in flames before it even gets off the ground.

3) Fire up the entrepreneurial imagination with a big cash bonanza along the lines of the X-Prize. Maybe one of the Forbes billionaires would be willing to dig into the petty cash box and offer up a $100 million reward to any group that can develop a method to permanently modify somatic cell genes with high safety and efficiency. The exact details of what constitutes a winning solution can be handled by whoever decides to put up the money. I would suggest that any person(s) willing to establish this prize stipulate, as a condition of the award, that the winner must offer to license the technology on a reasonable basis to other interested parties. This advance would be too important, the applications too widespread, to have it in the hands of a single group.

The approaches I’ve outlined above are not mutually exclusive. Having the U.S. government’s scientists competing against Celera to sequence the human genome drove both groups to put forth their best efforts, as well as explore different technological solutions to the problem. The most important thing here is to simply get started on this project ASAP.

Can throwing money at this problem solve it? I honestly don’t know. Others have advocated for Big Pharma to establish a general fund (not for a specific project) to invest in early biotech R&D efforts that would be capitalized with “billions of dollars”. This approach, however, would seem to be in conflict with the reality that many Big Pharma players have already established their own VC funds, or joined forces with VC firms to back these same types of companies. As a result, I’m not sure how easy it would be to get many companies on board with a strategy to simply fund early stage biotech. While this approach would certainly help to keep a number of struggling biotechs alive, sorting out the details is likely to be difficult given (1) the proposed level of funding, and the (2) disparate viewpoints currently held by Big Pharma members regarding the best way to enable future drug discovery.

Technological innovations take different forms. Some save money, such as an improved process for manufacturing larger amounts of recombinant proteins. Other advances save time, allowing the isolation of high-affinity monoclonal antibodies in a fraction of the time that it used to take. The technological advance that I advocate for here could be transformative, enabling treatments for literally thousands of diseases and improving the health of millions. The path forward will surely have difficulties and setbacks, numerous details will have to be worked out, and large egos will need to be crowded into small spaces. However, we must keep our eyes on the prize. As Nelson Mandela once put it, “It always seems impossible until it’s done.

Stewart Lyman is Owner and Manager of Lyman BioPharma Consulting LLC in Seattle. He provides strategic advice to clients on their research programs, collaboration management issues, as well as preclinical data reviews. Follow @

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  • http://www.genetic.org James Moore, Executive Director, KS&A

    I am the executive director of KS&A, the world’s oldest and largest organization dedicated to X and Y chromosome variations (sex chromosome aneuploidy)–including 47,XXY and the related package of symptoms known as Klinefelter Syndrome.

    At the moment, there is only one definitive post-natal test for these conditions: a genetic test called a karyotype. Since early diagnosis creates opportunities for early interventions and therapies that significantly improve outcomes, KS&A is eager for the introduction of widespread genetic testing, both prenatal and newborn screenings, that will identify these conditions.

    James Moore
    Executive Director
    KS&A
    P.O. Box 461047
    Aurora, CO 80046-1047
    jmoore@genetic.org
    http://www.genetic.org
    Toll-Free Helpline: 888-999-9428 (Denver/International: 303-400-9040)

  • yang xie

    many that are discussed above are also true for the therapeutic innovation in all diseases indications. people have the impression that drug r&d is such a huge undertaken with big many risks every step of the way, not to mention the big bucks needed or even wasted to support it. if a mission is too big to handle for a single stakeholder, what you do? you break it down to smaller incremental pieces, letting each party focus on few one of them, with a relatively foreseeable exit to meet their financial goals. Or we should focus on creating some intermediate mechanism, e.g. incubator, that bring together different players with a reduced risk or financial burden for each party. In the end, as is always said, people have no problem paying for success. With that said, all we need to focus is how to make real improvement by joining force, even in a incremental way.

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