BioScience Biz

FDA puts brakes on Geron stem cell trial--again

Last week the New York Times reported that the FDA put a clinical hold on Geron’s pioneering human embryonic stem cell (ESC) trial—before the first patient could be enrolled. In what was to be the world’s first clinical test of ESCs, Geron planned to differentiate the cells into neurons that can be injected into the spinal cords of paralyzed patients. However, the FDA requested more information after reviewing dose escalation data from pre-clinical animal studies.

This is the second time the FDA has delayed the Geron ESC clinical trial. Back in January, the FDA lifted an 8 months hold, allowing Geron to proceed with plans for the experimental injection of ESC-derived nerve cells into the spines of 8-10 paralyzed patients in attempt to repair the neural damage. The FDA was concerned over the safety of the protocol since the presence of any contaminating, undifferentiated ESCs could form tumors called teratomas.

In an announcement released Friday by Geron, the company explained that a recent animal study of the GRNOPC1 ESC therapy revealed the presence of “microscopic cysts in the regenerating injury site.” Fortunately the cysts were only found in the injection site and were non-proliferating. That is significant since it means that the cysts were benign, nevertheless, the FDA wants to look more closely at this development. 

"We have submitted these data to the FDA and are in discussions with the agency to answer its questions and proceed with the clinical trial," said the company in the release.

Researchers uncover possible link between avian flu and Parkinson's disease

Infection with the avian influenza virus might cause a predisposition to Parkinson's disease, according to research published this week in the Proceedings of the National Academy of Sciences. The following article is adapted from a recent report in The Scientist .

Epidemiological studies done in the 1980s showed that survivors of the 1918 Spanish influenza, a flu pandemic that killed more than 50 million people worldwide, had a greater incidence of Parkinson's disease later in life than the general population. Recent studies have suggested that the currently circulating strain of avian influenza has similar pathology to the 1918 flu. Though the subtypes of the viruses are different (Spanish flu shares the H1N1 subtype with the current H1N1 swine flu, whereas avian influenza has an H5N1 subtype), both viruses appear to enter the central nervous system (CNS) and can cause encephalitis, or inflammation of the brain. The study did not look at the ability of the current H1N1, or swine flu strain, to infect the CNS.

Richard Smeyne at St. Jude's Hospital in Memphis, Tennessee, and colleagues infected mice with avian flu and tracked how the infection progressed to the nervous system. "We thought [the virus] would get in [to the CNS] via the blood stream," through the blood brain barrier, said Smeyne. Instead, the virus entered "in a backdoor way," infecting the axon terminals of peripheral neurons first, specifically those of the gut and lung. The virus then traveled from the axon to the neuron cell body, where the researchers think it may be able to infect other neurons to eventually arrive in the brain.

Strikingly, said Smeyne, "this virus was mimicking the pattern of progression of Parkinson's disease." Some scientists think that Parkinson’s disease starts in peripheral neurons and slowly makes its way into the CNS, much like the progression of the flu infection. "It is interesting to me," said Tansey, that the virus "clearly infects the areas that are the most sensitive to chronic inflammation," such as the midbrain, where much of the neuronal death seen in Parkinson's disease occurs.

Smeyne observed a loss of about 17% of dopamine-producing neurons in the infected mice. Parkinson's patients normally lose between 50-80% of their dopamine-producing neurons, and the loss in Smeyne's mice suggests a predisposition to the disease, he said. Although all traces of the virus were cleared from the brain after about 20 days, and there was no evidence of further neuron loss, the virus appeared to have caused a prolonged activation of microglial cells, the immune cells that mediate inflammation in the brain. That effect -- observed 90 days post-infection -- suggests that these cells had become much more sensitive to subsequent neural insults, said Smeyne.

The biggest risk factor for Parkinson's disease, said Smeyne, is age. "We think what is happening with the influenza is that it's shifting the curve" to speed the onset of the disease. Tansey cautioned, however, that the study doesn't indicate the virus necessarily causes Parkinson's, nor does it suggest that more common strains of influenza may predispose people to the disease. It would be interesting to test whether the flu-infected mice would be more likely to develop full-blown Parkinson's disease if they were allowed to age, she said, and to repeat the study in non-human primates.

STUDY SUGGESTS H1N1 VIRUS MORE DANGEROUS THAN SUSPECTED

MADISON, WI - A new, highly detailed study of the H1N1 flu virus shows that the pathogen is more virulent than previously thought.

Writing in a fast-tracked report published recently (July 13, 2009) in the journal Nature, an international team of researchers led by University of Wisconsin-Madison virologist Yoshihiro Kawaoka provides a detailed portrait of the pandemic virus and its pathogenic qualities.

In contrast with run-of-the-mill seasonal flu viruses, the H1N1virus exhibits an ability to infect cells deep in the lungs, where it can cause pneumonia and, in severe cases, death. Seasonal viruses typically infect only cells in the upper respiratory system.

"There is a misunderstanding about this virus," says Kawaoka, a professor of pathobiological sciences at the UW-Madison School of Veterinary Medicine and a leading authority on influenza. "People think this pathogen may be similar to seasonal influenza. This study shows that is not the case. There is clear evidence the virus is different than seasonal influenza."

The ability to infect the lungs, notes Kawaoka, is a quality frighteningly similar to those of other pandemic viruses, notably the 1918 virus, which killed tens of millions of people at the tail end of World War I. There are likely other similarities to the 1918 virus, says Kawaoka, as the study also showed that people born before 1918 harbor antibodies that protect against the new H1N1 virus.

And it is possible, he adds, that the virus could become even more pathogenic as the current pandemic runs its course and the virus evolves to acquire new features. It is now flu season in the world's southern hemisphere, and the virus is expected to return in force to the northern hemisphere during the fall and winter flu season.

To assess the pathogenic nature of the H1N1 virus, Kawaoka and his colleagues infected different groups of mice, ferrets and non-human primates - all widely accepted models for studies of influenza - with the pandemic virus and a seasonal flu virus. They found that the H1N1 virus replicates much more efficiently in the respiratory system than seasonal flu and causes severe lesions in the lungs similar to those caused by other more virulent types of pandemic flu.

"When we conducted the experiments in ferrets and monkeys, the seasonal virus did not replicate in the lungs," Kawaoka explains. "The H1N1 virus replicates significantly better in the lungs."

The new study was conducted with samples of the virus obtained from patients in California, Wisconsin, the Netherlands and Japan.

The new Nature report also assessed the immune response of different groups to the new virus. The most intriguing finding, according to Kawaoka, is that those people exposed to the 1918 virus, all of whom are now in advanced old age, have antibodies that neutralize the H1N1 virus. "The people who have high antibody titers are the people born before 1918," he notes.

Kawaoka says that while finding the H1N1 virus to be a more serious pathogen than previously reported is worrisome, the new study also indicates that existing and experimental antiviral drugs can form an effective first line of defense against the virus and slow its spread.

There are currently three approved antiviral compounds, according to Kawaoka, whose team tested the efficacy of two of those compounds and the two experimental antiviral drugs in mice. "The existing and experimental drugs work well in animal models, suggesting they will work in humans," Kawaoka says.

Antiviral drugs are viewed as a first line of defense, as the development and production of mass quantities of vaccines take months at best.

In addition to his appointment at UW-Madison, Kawaoka also is a professor at the University of Tokyo. The new study was funded by grants from the U.S. National Institutes of Health, and the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Caption: The pandemic H1N1 flu virus (red) has been shown to be more virulent than scientists previously believed. The filamentous shape of the virus, which in this image have recently budded from infected cells, is also unusual.

© 2009 Steven S. Clark, PhD, some rights reserved.  Articles contained herein, are meant to be distributed freely to interested parties. However, any use, including excerpts from any article, must credit Steven S. Clark and provide a link to the original article published in BioScience Biz.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

VC funding is up for 2Q 2009

OnBioVC.com recently reported on the trends of international VC bioscience funding for the 2Q 2009 and found that there were 88 financings for 2Q09 versus 71 deals in 2Q08. The combined second quarter 2009 bioscience investment totaled approximately $1.7B, an increase of roughly $538.2M compared to the second quarter of 2008, or a ~31% boost.

Other tidbits follow:

• The largest deal of 2Q09 went to Boulder, CO-based Clovis Oncology which closed a $145M Series A financing (really!).


• In the three month period, 11cardiovascular device deals closed, accounting for $178.9M

• There were 41 total device deals representing 47% of 2Q09 financing.

• California continued its dominance in attracting investment dollars. The state was home to 22 financings for 2Q09 for a total of $493.2M.

• After California, the most active region was outside the US where 13 financings added up to $167.5M in investment.

• The biopharma sector attracted the most investment dollars ($868.2M), narrowly out-raising medical device deals ($743.6M).

• Biofuels accounted for $85.0M and diagnostic deals raised $16.8M.

Read the entire report here.

What’s new in stem cell research and therapy?

Stem cells are being tested in cardiovascular disease, stroke, diabetes, eye disease, Parkinson’s and to grow cartilage in damaged joints. Stem cells are also being made from blood, attached to sutures and authorities in Hungary crack down on unethical “stem cell tourism”.  Read about these and other recent advances in stem cell science here…

Is Alzheimer's caused by a presynaptic deficit in calcium mobilization?

This is adapted from a post by Jef Akst in The Scientist.

Researchers report a possible step forward in understanding the origins of Alzheimer's disease. Two genes that are commonly mutated in the early-onset form of Alzheimer's may cause the disorder by altering how presynaptic neurons release neurotransmitters, according to a study published this week in Nature.

The mechanism may apply to other neurodegenerative disorders as well, the researchers say.

"This is a new concept that's interesting to know," said molecular neurobiologist Ilya Bezprozvanny of the Southwestern Medical Center at Dallas, who was not involved in the work.

More than 100 different mutations in two genes coding for the proteins, presenilin 1 and 2, are associated with early-onset Alzheimer's disease, but the exact effects of these mutations on neural function is still unclear. "It's the first [study] suggesting that presenilins play a presynaptic role," Bezprozvanny said.

In 2007, molecular geneticist and neuroscientist Jie Shen of Harvard Medical School and her colleagues created knockout mice that lacked both presenilin genes and found memory deficits and neurodegeneration in the brain -- two key features of Alzheimer's disease. In the current study, Shen set out to determine on which side of the synapse presenilins exert their effect by creating two strains of knockouts: one that lacked both presinilin genes only in the presynaptic neurons in the hippocampus -- a brain region that plays an important role in memory -- and another where the genes were knocked out just post-synaptically.

Measuring neural activity in dissected brain sections from the two strains of knockout mice, the researchers were able to compare the effects of presenilins on pre- and post-synaptic activity. In presynaptic presenilin knockout mice, the researchers found drastically reduced long-term potentiation (LTP) -- a physiological measure of memory formation. In postsynaptic presenilin knockouts, however, LTP was normal.

Knocking out presynaptic presenilins also altered other aspects of neuronal function and reduced the probability of neurotransmitter release. "Our earlier work led us to focus on NMDA receptors, which are postsynaptic receptors," Shen said. "This [work] led us to see the importance of the presynaptic function."

Neurotransmitter release depends on increases in calcium levels within the presynaptic neuron. By blocking the release of calcium from the endoplasmic reticulum -- an intracellular source of calcium -- the researchers mimicked the effects of the presynaptic presenilin knockouts in control mice. This result points to intracellular calcium mobilization as a possible mechanism by which presenilins regulate neuronal function.

"The main take home message is there is a difference in the way neurons process calcium levels in absence of presenilins, and that has an effect on synaptic [function]," said Bezprozvanny. However, he cautioned, it's not clear how directly the findings can be applied to Alzheimer's disease. "This is not an Alzheimer's mouse model. This is a presenilin knockout."

Researchers studying neurodegenerative diseases have long debated whether knocking out these genes is a good model for Alzheimer's because the exact role of the many presenilin mutations associated with the disease is unclear. Some argue that these mutations result in a 'loss of function,' in which case a knockout model would appropriately represent the changes that occur in Alzheimer's patients. Others argue that these mutations result in a 'gain of function,' or a change that cannot be replicated by knocking out the genes entirely.

If patients with Alzheimer's disease do indeed have non-functioning presenilin genes, the results of this study may suggest that presynaptic neurotransmitter release is a more general mechanism of neurodegenerative diseases. For example, Shen and her colleagues found a presynaptic effect in a mouse model of Parkinson's disease. These changes "might be a precursor to neurodegeneration," Shen said, and might therefore provide new targets for disease therapies.

SBIR Reauthorization—Déjà vu All Over Again

I could probably just repost my earlier updates on the progress of the SBIR reauthorization because nothing really changes much. It looks like we are going to get another continuing resolution while the House tries an end-run around Nydia Vazquez’s (D-NY) stonewalling as I described in my earlier post here.

The Small Business Technology Council issued the following notice yesterday:

The Senate passed a continuing resolution on Friday that would extend the SBIR program another two months. That would make the new expiration date for the SBIR program September 30th, 2009. This CR also needs to pass the House of Representatives to be enacted, and we expect it to pass the House on Tuesday.

Currently, the staff from the House Small Business and Science Committees are in negotiations in conference with the staff from the Senate Small Business Committee to produce a compromise SBIR reauthorization bill that will incorporate elements from both the House and the Senate Reauthorization Bills. We have heard and have reason to believe that both sides are negotiating in good faith, and that no party is acting unreasonably or otherwise sabotaging the process. Because there is an agreement between the staffers in the conference, we won't know what's in the compromise bill until it is finished and released to the public.

The SBTC will be hosting a conference call on Thursday to discuss these developments. Contact Alec Orban if you'd like the call-in number and code

Stay tuned or follow the tortuous path of this legislation at www.SBIRreauthorization.com.

The SBIR Clock is Ticking

Members of the Senate Small Business and Entrepreneurship Committee and the House Small Business, and Science and Technology Committees are meeting, yet again, to see if this time they can resolve the impasse of two very different SBIR reauthorization bills, (Senate S.1233 and House H.R.2965).

You will recall that Rep. Nydia Velazquez (D-NY), chairwoman of the House Small Business Committee, holds the very anti-small business view that VC-owned technology companies should be able to participate fully in SBIR/STTR competition. Amazingly, she has for the last two years, prohibited any testimony on behalf of small businesses in her committee and also on the floor of the House. In contrast, the Senate’s bill preserves most of the SBIR program for small company by capping participation of VC’s, a compromise that last year was agreeable to both the VC and small business lobbies. But the Velazquez would not budge from her position.

Will this year be different?

When the full House considered its SBIR reauthorization bill, Velazquez got the Rules Committee to prohibit consideration of a Edward Markey (D-MA)-led amendment that would have made the bill similar to the Senate version. She did this because it was widely expected that the Markey amendment was favored by most members of the House and would have passed.

Several House members, led by Markey, who disagree with the obstructionist Velazquez and do not like her bullying, are trying an end run around her by sending a letter to Senator Mary Landrieu (D-LA), Chair of the Senate Small Business and Entrepreneurship Committee, expressing their support for the Senate’s SBIR reauthorization bill. This letter represents an attempt to let the Senate conference committee members know that most Representatives disagree with Velazquez’s bill.

The more members of the House who sign the letter, the greater chance that the conference committee will approve S.1233 as the final version. You can help by emailing the Markey letter to your Representative and ask that s/he sign on this week. Time is of the essence since an acceptable compromise must be made by next Tuesday, July 28. While you are at it, ask your Rep to consider how they are going to explain to small businesses in their state why they voted against small businesses so that rich VC’s could have access to more Federal funds.

SBIR updates and links for contacting your Representatives and Senators can be found on www.SBIRreauthorization.com.

© 2009 Steven S. Clark, PhD, some rights reserved.  Articles contained herein, are meant to be distributed freely to interested parties. However, any use, including excerpts from any article, must credit Steven S. Clark and provide a link to the original article published in BioScience Biz.

Disclaimer: The authors used their best efforts in collecting and preparing the information published herein. However, neither Steven S. Clark, nor other authors, assume, and hereby disclaim, any and all liability for any loss or damage caused by errors or omissions, whether such errors or omissions resulted from negligence, accident, or other causes.

SBIR re-authorization update

The House just passed a controversial SBIR reauthorization bill with the usual shenanigans by Rep. Nydia Velazquez (D-NY). As in last year’s reauthorization debacle, Ms Velazquez completely stifled any testimony contrary to her preferences. The major point of contention is whether to allow companies that are majority-owned by VCs to be eligible for SBIR funding—currently they are not. Even though Velazquez chairs the Small Business Committee, through which the bill passed, the small business lobby was not allowed any input on the bill. Velazquez wants VC owned companies to share in the SBIR pool, which, as opponents point out will limit money available for not-as-well funded companies. The argument against doing this is that the earliest stage companies, which are not likely to attract VC funding will suffer the most from this diversion of funds.

Perhaps they ought to change the name of Velazquez’s committee to the VC Business Committee. She certainly is not representing small businesses here.

The devilish details

The following details of the House’s actions are modified from a posting by Rick Shindell, aka the “SBIR Insider”.

The SBIR Program was created by the Small Business Innovation Development Act of 1982. Every few years, the SBIR program must be “reauthorized” by Congress or it will cease to exist. Reauthorization was enacted in 1986, 1992, and 2000 and was slated again for September 2008; but, instead, the program was temporarily extended by a continuing resolution (CR) to March 20, 2009 and again to July 31, 2009.

Although H.R. 2965, "Enhancing Small Business Research and Innovation Act of 2009," passed on the House floor, any opportunity for discussion or vote on compromise amendments that Ms Velazquez did not favor were summarily dispatched by the House Committee on Rules. The rules committee, led by chairwoman Louise Slaughter (D-NY), under a "closed rule" allowed only 5 of 34 amendments to be ruled "in order" and brought to the floor. The amendments mostly spelled out small things like SBIR award preferences for minority and woman owned businesses and for businesses in economically depressed areas.

The big surprise was the committee's "out of order" ruling of the compromise amendment from Ed Markey (D-MA), Niki Tsongas (D-MA), Peter Welch (D-VT) and Paul Hodes (D-NH). The amendment would put a ceiling on VC awards (similar to what the Senate favors), and increase award sizes to $150K for Phase I, and $1M for Phase II. Reportedly, this amendment has strong bipartisan support in the House and would have passed if a vote was allowed. This would have been a major embarrassment to Velazquez, and perhaps the House leadership.

What next?

The bill now goes to the Senate which has passed its own version that was sponsored by Russ Feingold (D-WI). As mentioned, the Senate version contains several attractive features that Velazquez has not supported in the past. These include a significant increase in the award size and in the total SBIR set-aside, as well as the compromise cap on the number of awards to VC owned companies. Ultimately there will be a conference committee of the House and Senate that will either hammer out a compromise bill, or, once again, fail to reach an agreement, whereby the decision for another Continuing Resolution (CR) either will be considered, or the SBIR program will lapse (STTR is good through September 30, 2009). Something needs to be done by the end of this month.

You are encouraged to contact your congressional representatives to urge them to take action to ensure that the SBIR program does not die from neglect (or abuse). Here is an old template of a suggested letter you can update and send to your Representative and Senators. If you are worried about the SBIR grant application you plan to submit soon, you might consider sending a letter to every member of the House Small Business Committee.

Tell them what an important “stimulus” the SBIR program is for small business development and job creation. That ought to get their attention.

Clinical research activity up significantly in 2008

According to a report in FierceBiotech, surprising news came out of the recently completed 45th Annual Meeting of the Drug Information Association (DIA).  Despite cutbacks in the international biopharma industry, clinical trial activity was up in 2008. Overall, 795 new clinical trials were launched in 2008, compared with 662 that were initiated in 2007. There were 5,700 active INDs in 2008, which represents a greater than 20 percent increase over the 4,744 INDs active by the end of 2007—a substantial increase.

Trial activity was also assessed by the number of new FDA form 1572s, which all clinical investigators on FDA-approved trials sign as a promise that he will abide by the federal guidelines set forth in the Code of Federal Regulations for the use of drugs in an investigational setting. The FDA registered 23,827 new 1572s from clinical investigators in 2008, up 5.8 percent from the previous year. However, the number of new 1572s from China-based clinical investigators fell 30 percent due to the long approval process, but Indian-based 1572s rose 14 percent. South Korean investigators submitted 74 percent more 1572s while submissions from Taiwan rose 21 percent. Clinical trial activity is also up in Eastern Europe where the FDA saw significant increases from Russian investigators (20 percent), as well as Romanian (44 percent), Polish (17 percent) and Bulgarian (57 percent) clinical researchers.

It will be interesting to see the data for 2009.

DIA is a professional association of more than 18,000 members worldwide who are involved in the discovery, development, regulation, surveillance, or marketing of pharmaceutical products. The DIA annual meeting is the biopharmaceutical industry's largest, longest running, international event.