New gene found for late-onset Alzheimer’s (OnThePharm (Hanser)) by RJS

Researchers working out of CUMC, BU School of Medicine, and the University of Toronto have discovered a second major gene responsible for the development of late-onset Alzheimer’s (and the fifth Alzheimer’s gene overall).

Variants of the SOR1 gene were found to be more common in people with late-onset Alzheimer’s than in healthy people of the same age. It’s believed that these genetic variants alter the normal function of SOR1 and send APP down a pathway that increases the production of the toxic amyloid beta peptides in the brain. When SOR1 is working properly, it sends APP along recycling pathways which keeps it from being cut into the more toxic forms and killing neurons.

Also significant is the fact that this gene has been replicated in four distinct ethnic groups — Caribbean-Hispanics, North Europeans, African-Americans and Israeli-Arabs — rather than relying on data from caucasians.

This is very exciting news for Alzheimer’s research, and brings us closer to having a better overall picture of how the disease works. Understanding of the SOR1 variants’ precise role in the disease is still unknown. Researchers are still unclear which alterations cause APP to go down the amyloid beta pathway.

There are some other findings of note in this study more in the realm of genetics and sociology than pure Alzheimer’s research, that might probably have been worth noting on their own had this discovery not been overshadowed by this Alzheimer’s breakthrough. There are some indications that generations ago, Israeli-Arabs and Carribean-Hispanics may have been genetically or geographically linked, since the same SOR1 variant was found in both groups:

In total, the initial discovery group included 350 families (representing a total of 1,800 people, half of whom had Alzheimer’s), from Columbia University Medical Center and the University of Toronto. The group was divided into two parts: one that was analyzed to help with the discovery of SORL1, and a second that was analyzed to confirm the role of the gene. To this collection, Dr. Farrer, from Boston University School of Medicine, added 500 African-American sibling pairs (representing a total of 1,000 people), where one sibling was diagnosed with Alzheimer’s and the other was not. Farrer also enabled the researchers to reconfirm their findings in an examination of data from Israeli-Arabs, while Younkin’s data from mostly white Alzheimer’s patients provided by the Mayo Clinic also confirmed the findings. Interestingly, the same variant was found in both the Israeli-Arab and Caribbean-Hispanic groups, which indicates that generations ago these two groups may have been genetically or geographically linked.

Technorati Tags: Medicine, Alzheimer’s, aging, genetics, sociology, SOR1

Genentech buys a pipeline (OnThePharm (Hanser)) by RJS

Looks like Genentech just bought themselves all the IP associated with an unnamed cancer target from Amphora Discovery Corp. Once again, buying a pipeline instead of developing it.

But hey, small companies have always been better at innovation than big companies.

Technorati Tags: Medicine, pharmacy, cancer, oncology, Genentech, Amphora

More on reversing Type 1 diabetes (OnThePharm (Hanser)) by RJS

This past summer, I went on an article-printing spree, and one of the things I printed was this NYTimes article about the work of Dr. Denise Faustman, a diabetes researcher out of MGH in Boston. I read it early last week, and had been idly wondering what became of her research, thinking I should dig and see if anything newer had happened. Fast-forward to last night, I was cruising digg, and I came across more results involving the same protocol that she used back in 2003.

In March of this year, three other labs confirmed that Dr. Faustman’s protocol could reverse Type 1 diabetes in non-obese diabetic (NOD) mice. Those results were inconclusive on the role of spleen cells in the recovery of insulin-producing pancreatic islets. The new data from the NIH provide a fourth confirming study, and more significantly, the role of spleen cells in islet regeneration.

In the 2001 and 2003 studies, Faustman and colleagues treated end-stage nonobese diabetic (NOD) mice with Freund’s complete adjuvant, a substance that suppresses the activity of the immune cells that destroy islets in type 1 diabetes. They also introduced donor spleen cells to retrain the immune system not to attack islets and found that the protocol not only halted the immune destruction caused by diabetes but also allowed the insulin-producing pancreatic islet cells to regenerate. Evidence indicated that the spleen cells were the source of at least some of the regenerated islet cell and hastened the restoration of blood sugar levels.

The direct contribution of spleen cells to islet recovery, first described in the 2003 study, is confirmed in the current work. NIH researchers used cell lineage tracking in the form of Y-chromosomal fluorescence in situ hybridization (FISH), in combination with insulin staining, to follow the fate of male spleen cells transplanted into female recipients. The female mice that received male donor cells consistently showed Y-chromosome-positive insulin-producing islet cells, indicating that the introduced spleen cells contribute to islet recovery. The current study also showed that the degree of spleen cell contribution is influenced by mouse age at the start of treatment. Spleen cells appear to contribute to islet recovery more in mice who are older and with more advanced diabetes compared with younger mice with less advanced diabetes, in which regeneration of remaining islets may be the dominant mechanism.

With four studies confirming the success of the diabetic reversal, I am wondering when Phase I human trials will begin. From an economic standpoint, FCA and BCG are both good choices, since they are both orphaned drugs. FCA is incredibly old — Dr. Freund, the guy who created it, died in 1960.

While I’m glad to see the success of these studies, it’s still a long way from mice to people. I have my doubts about the side effect profile of this treatment as well. FCA is a biologic made (usually) from killed M. tuberculosis, and is forbidden for use in humans. It has a high incidence of painful reaction and potential tissue damage. So that leaves BCG, a similar, but less potent biologic made from M. bovis, found in TB vaccines. The NYT article states that BCG was used in Dr. Faustman’s 2003 work, but the original research paper (PDF) indicates that it was actually FCA.

This leaves me wondering two things: 1) will BCG have a similar effect and 2) if BCG is not successful, will FCA be approved for use in humans?

Technorati Tags: Medicine, diabetes, type 1 diabetes, fca, bcg, biochemistry, physiology

Gleevec shown to prevent rheumatoid arthritis in mice (OnThePharm (Hanser)) by RJS

This is somewhat unexpected:

Although there are two documented cases in which individuals taking imatinib to treat their cancer showed clinical improvement in their RA, there had been no study of the effects of imatinib in a mouse pre-clinical model of RA. So, William Robinson and colleagues administered imatinib to mice with an RA-like disease. Imatinib both prevented the onset of disease and the development of established disease. It did this by inhibiting the function of many of the immune cells that contribute to disease in patients with RA. Importantly, imatinib was also shown to inhibit the proliferation of cells taken from the joints of patients with RA. This study indicates that imatinib might provide relief to the many individuals suffering from RA.

Somewhat unrelated, but what would you do for a patient who develops RA after he starts treatment for his newly-discovered HIV? Talk about contraindications!

Technorati Tags: Medicine, pharmacy, Gleevec, rheumatoid arthritis, arthritis

Remicade (infliximab) for ulcerative colitis (OnThePharm (Hanser)) by RJS

I’ve got a soft spot in my heart for GI disorders since I suffer from one myself. They suck. So when I read this the other day I was a bit surprised.

“For people with active ulcerative colitis who do not respond to corticosteroids or immunosuppressive agents, infliximab is effective in inducing clinical remission, inducing clinical response, promoting mucosal healing and reducing the need for colectomy, at least in the short term,” said review co-author Dr. Anthony Kwaku Akobeng.

[…]

“Infliximab is another option if steroids fail,” said Peter Higgins, M.D., an assistant professor in gastroenterology at the University of Michigan Medical Center in Ann Arbor.

And here I was, thinking this was common knowledge. In fact I during my hospitalization a few weeks ago whilst on vacation I had a discussion about UC with the tech doing my CT scan. She was telling me one of her friends had severe UC, and that he was on steroids. I distinctly remember suggesting Remicade or Humira instead of prednisone through my drug-induced stupor. She was telling me he hated the side effects. What a surprise. Then I think I started rambling about monoclonals and the lack of a generic approval pathway for biologics in general. She stopped talking to me after that.

She was cute, too. Really cute.

But hey, more studies are always good. Too bad Remicade is WAY more expensive than prednisone…

Technorati Tags: Medicine, pharmacy, Remicade, infliximab, ulcerative colitis

Dapoxetine for premature ejaculation (OnThePharm (Hanser)) by RJS

Dapoxetine, an SSRI patented by ALZA pharmaceuticals is showing some real promise combatting premature ejaculation. Dapoxetine, of course, has been around for a little while, though it’s not available yet by prescription. (It’s currently in Phase III trials.)

The analysis involved over 2600 men with moderate to severe premature ejaculation and their partners. Patients were randomly assigned to receive placebo (870), 30 mg dapoxetine (874), or 60 mg dapoxetine (870) and were instructed to take a dose 1-3 hours before sexual intercourse. On average, at the start of the study, the men ejaculated under a minute after penetration. The researchers found that after 12 weeks the time to ejaculation was 1.75 minutes for placebo, 2.78 minutes for 30 mg dapoxetine, and 3.32 minutes for 60 mg dapoxetine.

Not being a lifestyle drug player-hater, I’m happy to see some progress being made on premature ejaculation. Count me as one person who had no idea it was so common. As with erectile dysfunction, I’m happy that these lifestyle afflictions — which I’m sure are traumatic for these men and their partners — are treatable. By the same token, I’m glad that we’ve reached a point in time where things like erectile dysfunction and premature ejaculation are now treatable. Some would have us go back to the dark ages ignoring these “umimportant” problems, but I think it’s nice that we are in a society that can afford to do life-saving research and life-enriching research simultaneously. Though, like many other medical professionals, I sometimes wonder if one is being done at the expense of the other.

[Image from ScienceBase]

Opening therapeutic doors with ultrasound (OnThePharm (Hanser)) by RJS

Researchers have shown how ultrasound energy can briefly “open a door” in the protective outer membranes of living cells to allow entry of drugs and other therapeutic molecules – and how the cells themselves can then quickly close the door. Understanding this mechanism could advance the use of ultrasound for delivering gene therapies, targeting chemotherapy and administering large-molecule drugs that cannot readily move through cell membranes.

Using five different microscopy techniques, the researchers showed that the violent collapse of bubbles – an effect caused by the ultrasound – creates enough force to open holes in the membranes of cells suspended in a liquid medium. The holes, which are closed by the cells in a matter of minutes, allow entry of therapeutic molecules as large as 50 nanometers in diameter – larger than most proteins and similar in size to the DNA used for gene therapy.

“The holes are made by mechanical interaction with the collapsing bubbles,” said Mark Prausnitz, a professor in the School of Chemical and Biomolecular Engineering at the Georgia Institute of Technology. “The bubbles oscillate in the ultrasound field and collapse, causing a shock wave to be released. Fluid movement associated with the resulting shock wave opens holes in the cell membranes, which allow molecules from the outside to enter. The cells then respond to the creation of the holes by mobilizing intracellular vesicles to patch the holes within minutes.”

Transmission electron micrograph
showing a prostate cancer cell
immediately after exposure to
ultrasound. Image has been color
enhanced to show to the spot
where the cell membrane has
been removed.

Ultrasound is the same type of energy already widely used for diagnostic imaging. Drug delivery employs higher power levels and different frequencies, and bubbles may be introduced to enhance the effect.

Ultrasound drug delivery could be particularly attractive for gene therapy, which has successfully used viruses to insert genetic material into cells – but with side effects. It could also be used for more targeted delivery of chemotherapy agents.

“One of the great benefits of ultrasound is that it is noninvasive,” Prausnitz said. “You could give a chemotherapeutic drug locally or throughout the body, then focus the ultrasound only on areas where tumors exist. That would increase the cell permeability and drug uptake only in the targeted cells and avoid affecting healthy cells elsewhere.”

Researchers have only recently found that the application of ultrasound can help move drugs into cells by increasing the permeability of cell membranes. It had been hypothesized, but not definitively shown, that the ultrasound increased the permeability by opening holes in cell membranes.

Prausnitz and collaborators Robyn Schlicher, Harish Radhakrisha, Timothy Tolentino, Vladimir Zarnitsyn of Georgia Tech and Robert Apkarian (now deceased) of Emory University set out to study the phenomenon in detail using a line of prostate cancer cells. They used scanning and transmission electron microscopy of fixed cells and two types of optical microscopy of living cells to assess ultrasound effects and cell responses.

Scanning electron micrograph
showing a prostate cancer cell
immediately after exposure to
ultrasound. Image has been
color enhanced to show to the
spot where the cell membrane
has been removed.

Beyond demonstrating that ultrasound punched holes in cell membranes, the researchers also studied the mechanism by which cells repair the holes. After the ultrasound exposure, they introduced into the cell medium a chemical not normally taken up by the cells. By varying when the chemical was introduced, they were able to determine that most of the cells had repaired their membranes within minutes.

Though the researchers used prostate cancer cells in the study reported in the journal, they have also studied other types of cells and believe ultrasound offers a general way to briefly create openings in many classes of cells.

Researchers face a number of challenges, including FDA approval, before ultrasound can be used to deliver drugs in humans. For example, the effects of the ultrasound were not consistent across the entire volume of cells, with only about a third affected. Researchers will also have to address safety concerns and optimize the creation of collapsing bubbles – a phenomenon known as cavitation – within bodily tissues.

Beyond demonstrating that ultrasound punched holes in cell membranes, the researchers also studied the mechanism by which cells repair the holes. After the ultrasound exposure, they introduced into the cell medium a chemical not normally taken up by the cells. By varying when the chemical was introduced, they were able to determine that most of the cells had repaired their membranes within minutes.

Though the researchers used prostate cancer cells in the study reported in the journal, they have also studied other types of cells and believe ultrasound offers a general way to briefly create openings in many classes of cells.

Researchers face a number of challenges, including FDA approval, before ultrasound can be used to deliver drugs in humans. For example, the effects of the ultrasound were not consistent across the entire volume of cells, with only about a third affected. Researchers will also have to address safety concerns and optimize the creation of collapsing bubbles – a phenomenon known as cavitation – within bodily tissues.

“Before we can use ultrasound for therapy in the body, we will have to learn how to control the exposure,” Prausnitz noted. “If we can properly design the impact that ultrasound makes on a cell, we can generate an impact that the cell can deal with. We want just enough impact to allow transport into the cell, but not so much of an impact that the cell would be stressed beyond its ability to repair the injury.”

Researchers don’t yet know if the membrane holes cause long-term harm to the affected cells. General assays show that cells survive after resealing the membrane holes, but detailed studies of cell behavior are still needed. Evidence from other researchers suggests that cell membranes are frequently damaged and repaired inside the body – without long-term ill effects. That suggests cells may similarly tolerate ultrasound’s effects.

“One of the real challenges is going to be translating the successes that have occurred in the laboratory and in small animals into clinical success in people,” said Prausnitz. “Now that we better understand the mechanism of ultrasound’s effects, we can more effectively take advantage of it for medical therapy.”

[From a GA Tech press release]

Technorati Tags: Medicine, ultrasound, science, cancer, oncology

Gardasil working on more than the original 4 HPV strains (OnThePharm (Hanser)) by RJS

Looks like Gardasil may be effective against more than just the four most-prevalent HPV strains (16, 18, 6, and 11): it’s showing promise against strains 31 and 45 as well.

HPV types 16 and 18, which are directly targeted by Gardasil, are responsible for 75 percent of all cervical cancer. But scientists found the vaccine also induces an antibody response capable of neutralising strains 31 and 45, which together account for another 8 to 9 percent of cases.

It makes me wonder how much mindshare (and possibly marketshare) Cervarix — the GSK competitor to Gardasil — will garner when it’s approved by the FDA. GSK is going to have to work hard to differentiate its vaccine against Gardasil. They’ll certainly have their work cut out for them, because you can bet Merck will be testing Gardasil against the remaining 34 strains of HPV (which makes up only a tiny percentage of cases) to see if it has any success there as well. If I were GSK, I’d be thinking about getting some more clinical trials going on strains that Merck isn’t playing with yet.

Technorati Tags: Medicine, pharmacy, Cervarix, Gardasil, HPV, cancer, oncology

Vioxx as cancer prevention (OnThePharm (Hanser)) by RJS

Merck lost their latest Vioxx lawsuit while I was away on my vacation. I didn’t care enough to delve into the details, but as someone who thinks rofecoxib should be put back on the market, I thought this new research out of Dartmouth was worth a look. It seems that Dr. John Baron has experimented with rofecoxib as a chemopreventative in the fight against colorectal cancer, with some success. (PDF)

The findings indicate that rofecoxib decreases the incidence of adenomas (polyps) in healthy people as opposed to just those who have familial adenomatous polyposis (FAP), a genetic disorder. Not surprisingly, the 3 year study was funded by Merck before the drug was pulled from the market.

In the year following three years’ treatment, patients taking rofecoxib experienced a slightly increased risk of any adenoma, but not of advanced adenomas. However, over the entire length of the trial (three years of treatment and one year off drug), patients taking rofecoxib experienced a reduction of the risk of any adenoma.”

Not all was rosy, though. From the discussion:

Given the toxicity associated with the use of rofecoxib, it is unlikely to be attractive for chemoprevention, but it is tempting to conclude that sustained use of other NSAIDs would permit increased surveillance intervals (in the expectation of reduced risks of colorectal cancer) and reduce risks from polypectomy. However, even proven efficacy of these drugs would not automatically justify their wide use for chemoprevention. The cardiovascular effects of non-aspirin NSAIDs are not well understood, and serious gastrointestinal toxicities may be an issue. Potential toxicities of NSAIDs will need to be weighed against their benefits in the context of the risk reduction already provided by periodic surveillance colonoscopy and polypectomy.

Technorati Tags: Medicine, pharmacy, Vioxx, rofecoxib, Merck, cancer, oncology

Lack of economic demand for infectious disease hurting research (OnThePharm (Hanser)) by RJS

Lots of times when I read press releases, snarky headlines pop into my head, particularly when something seems so painfully obvious you wonder why someone spent their time and money researching the topic. But then I stop and think about the Greek philosophers, and how evidence-based science came to topple some of the most strongly held beliefs of the age. Think Galileo’s observations of falling objects, for example. Then of course, there’s the whole study of probability. If you’ve ever spent more than a week in a probability course, you quickly discovered that intuition is often wrong. Until you develop it further and start to understand how things actually are rather than how they appear to be.

Anyway, I’m getting off-track here. It’s this train of thought that has prevented me from making fun of scientific research. It’s always good to have data to back up your claims because we know that common sense is often not common, or sense.

Research out of the Economic and Social Research Council in the UK indicates that despite increases in drug development for infectious diseases like Malaria, TB, Sleeping Sickness, etc., overall progress is being hampered because there’s just not much economic incentive to invent new therapies. This isn’t news to anyone who follows the drug industry of course, but maybe it is to some politicians somewhere. It’s no secret the lifestyle drugs are often more profitable than life-saving treatments for infectious diseases because the relatively rich people in first-world countries can pay more than an African farmer bringing in $300/year.

The study suggests private-public partnerships (PPPs) to help the problem. Other companies, like Napo Pharmaceuticals, are taking a different approach to drug development banking on an inexpensive treatment with super-wide appeal to make money. Think of it as the Henry Ford way of doing business in a cash-strapped third world. Both ideas are intriguing, but I think the PPP route ultimately will have more traction. In a cash- and research-intensive field like drug discovery, adopting an unprone business models involves a bit more risk than a rich, first-world investor looking to make a buck is willing to take. It’ll be up to organizations like the Gates Foundation to pick up the slack left behind by the for-profit sector.

[Image: Trypanosomes surrounded by red blood cells from Nature — larger image here]

Technorati Tags: Medicine, pharmacy, economics, research, healthcare, infectious disease