Precise engineering of the genomes of mammalian cells enabled biological and medical applications researchers had dreamed of for decades. Recent developments in the stem cell field have created even more excitement for genetically modifying genomes because it enables delivering more beneficial stem cell-derived therapeutic cells to patients . For instance, by correcting a gene mutation known to be critical to Parkinson’s disease, LRRK2 G2019S, in patient-specific iPSCs (induced pluripotent stem cells), it appeared possible to rescue neurodegenerative phenotypes .
Significant amount of fund and energy had been invested in technologies such as ZFN and TALEN, however, judging from the explosion of publications and business activities in just about 2 years since the illustration of its mechanism (just today, Jan 8th, 2015, Novartis announced CRISPR collaborations with Intellia, Caribou, applying it in CAR T cell and HSCs), the CRISPR/cas system is the rising star. This system uses a guide RNA to direct the traffic of a single nuclease towards different targets on a chromosome to alter DNA sequence through cutting. The nuclease, cas9, can be mutated from a double-stranded DNA endonuclease to a single-strand cutter or a non-cutting block, or further fused to various functional domains such as a transcription activation domain. This system can also be used to edit RNA molecules.
A weak spot on the sharp blade of CRISPR is, like any methods for creating loss-of-function effects (RNAi if you remember), the potential of off-target effects. While they can never be completely avoided, with the ever growing popularity of deep sequencing, at least we can know all unintended changes on the edited genome. Almost a perfect storm! As an interesting side story, when we at Allele Biotech first saw the paper in Science describing the CIRPSR/cas system , we immediately wrote an SBIR grant application for applying the bacterial system to mammalian cells. The first round of review in December 2012 concluded that it would not work due to eukaryotes’ compact chromatin structures. Of course, the flurry of publication in early 2013, while our application was being resubmitted, proved otherwise. The good news is, Allele Biotech still received an SBIR grant from NIGMS in 2014. Unlike most of the genome editing platforms known in the literature, our goal was to build an all-RNA CRISPR/cas system, thereby with higher potency, less off-target effects, and, as a footprint-free platform, more suitable for therapeutic applications. This system will be combined with our strengths in iPSC and stem cell differentiation, fluorescent protein markers, and deep sequencing based bioinformatics to improve cell therapy and cell based assays.
1 Urnov, F.D., et al., Genome editing with engineered zinc finger nucleases. Nat Rev Genet, 2010. 11(9): p. 636-46.
2 Reinhardt, P., et al., Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression. Cell Stem Cell, 2013. 12(3): p. 354-67.
3 Jinek, M., et al., A Programmable Dual-RNA-Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science, 2012.
SBIR/STTR/CPP EXPIRATION LOOMS (circulated by Rick Shindell, reposted by AlleleBlog)
The SBIR/STTR/CPP now appears likely to expire on Thursday night, September 30.
Some will deny it but here’s what’s happening.
Allegedly the Senate and House were close to a compromise complete with an 8 year
reauthorization of SBIR/STTR/CPP but each time it goes back to the House (Nydia &
Day), they change the VC language to masquerade 100% VC involvement as a compromise.
Because time is so short, the Senate passed a bill (S.3839) to simply extend
SBIR/STTR/CPP through January 31, 2010. The House was going to pass it on Wednesday
with the President signing Thursday. However, the word on the street is that Nydia
Velazquez, chair of the House Small Business Committee, and her illustrious second,
Michael Day, are rejecting the bill and are poised to let SBIR expire if necessary,
at least in the short term.
It seems that Velazquez’s hope is to move the SBIR reauthorization into the lame
duck session and incorporate all her Wall Street investors’ 100% non-compromise VC
ownership and jumbo award support into a must pass, end of the year omnibus bill
that can’t be touched by her detractors.
This sounds like a script for TV, but several years ago we had a similar year end
omnibus situation involving Nydia (as ranking member) and Sam Graves (subcommittee
chair) and BIO/NVCA, but the main difference was that the small business committee
chair was Donald Manzullo who nipped it in the bud. In our scenario today we have
to look to the House leadership to do it, but it will take your involvement.
Many senior people in the democratic party called for the House to support the
Senate compromise bill H.R. 2965, but Nydia ignored those calls, as did Jason
Altmire, the creator of this infamous Altmire Quagmire. Now Nydia’s really “miffed”
because last week she tried to “scrub” H.R.5297, the Small Business Jobs Act of
2010, but the Obama administration and Speaker Pelosi rolled her over and passed it.
CALL TO ACTION
If SBIR is important to you and your company, it’s time to get serious and realize
that this program can, and will go away unless you make a big noise to let your
politician’s know how you feel. All of us are sick of this, and we’re now facing a
lapse. Eight times this program has been deemed important enough to keep going (via
a CR) but will Nydia be successful in blocking this ninth attempt?
Voting will occur in the House on Wednesday and this may be the last time until
after the election that the SBIR extension bill could voted on. That means we must
act on Tuesday, September 28.
Here are some suggestions and rationale behind them.
CALL CALL CALL the House Tuesday September 21! Call Nancy Pelosi’s office at (202)
225-4965, Steny Hoyer (majority leader) at (202) 225-4131, Nydia Velazquez (202)
225-2361, also the House Small Business Committee line (202) 225-4038
Those of you who are good democrats, call the remaining House Democratic caucus
leaders: John Larson 202- 225-2265, Xavier Becerra 202-225-6235, Jim Clyburn
Those of you who are good republicans, call John Boehner (202) 225-6205, Eric Cantor
Tell them in your own words that SBIR is about to expire and is being held hostage
by Nydia Velazquez. Let them know how important continuation of SBIR is to your
business and the country. Ask them to please support S.3839 (additional temporary
extension of programs under the Small Business Act and the Small Business Investment
Act of 1958) to keep the program from lapsing this week.
I realize that I’m asking you to do something that requires a good chunk of your
time. However, at the risk of losing you as a reader I must tell you that I donate
a large share of my time to try and keep you informed about this program, and I’m
not asking you to do anything for me, only for you and others like you. We do have
some good representatives from both parties BUT they need to hear from you and
If you’re bold ask, “I would like to know how a party can let itself get hijacked by
a few people (like Nydia) on a vitally important, highly regarded and accepted
program. This action is to the detriment of your constituents, the country, and
yes, even your own party!”
Here’s what’s going on in the back rooms (formerly smoke filled) The Senate agreed
on a 4 month extension for SBIR because they (Senate) largely (including many on the
Republican side) did not feel a reasonable bill could be passed in the lame duck
session. The Senate has offered up some huge compromises that some believe even
James Greenwood from BIO could live with. The very long shot is that with enough
pressure we might get a compromise bill passed by Thursday.
WHAT HAPPENS IF SBIR LAPSES, EVEN FOR A SHORT TIME
This is an interesting question. Theoretically those projects (grants and
contracts) that are already in place should be okay, but some not. All new unsigned
agreements would stop. Agency comptrollers may start adjusting their budgets to put
the overall 2.8% SBIR/STTR back into their own research pools. Administrative
funding for SBIR could be severely cut back. Remember, all of your grants and
contracts are “subject to the availability of funding.”
On the other hand, SBIR can be voluntary, so some agencies may choose to keep their
SBIR doors open, hoping for, or expecting the reinstatement of the program.
In any event, this is bad for you and the agencies.
The Insider will be on the Hill Wednesday and Thursday, so we’ll do a follow up
report to you asap.
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The National Institutes of Health (NIH) just announced a new type of Small Business Innovative Research (SBIR) grants. Called SHIFT SBIR, these grants are designed to “(1) to foster research that is translational in nature and (2) to transform academic scientific discoveries into commercial products and services,” according to the NIH announcement, and to also facilitate licensing of intellectual properties from academic institutions as well as promote better access to academic resources. The PI transitioning from the academic institution must be primarily employed by his/her research institution at the time of application and must be primarily employed (more than 50% time) by the company by or at the time of award.
One very attractive aspect of these grants is that they mean more money than standard SBIR grants. Up to $200,000 total costs per year and time periods up to 2 years may be requested for Phase I. Well-justified budgets up to $750,000 total costs per year and time periods up to 3 years may be requested for Phase II. That is sufficient for a good researcher to build a team to do research in one direction within pretty much any small company setting.
A little background about SBIR grants: SBIR programs sponsored by federal funding agencies including the NIH, NSF, DOE, FDA, the military departments, etc. have been a major source of funding for many biotech companies like Allele Biotech during their startup phases. SBIR grants can also be used to facilitate continued research and help business expansion even as the company grows. As an example of the effects of SBIR grants, Allele Biotech obtained 5 such grants from 2000 to 2003 and built a company from just ideas to one with a patent in RNAi, an out-licensing deal with Promega, a product line in oligo synthesis, and a structure that helped launch currently ~1,500 products since 2004. We then carried out 2 more SBIR contracts for the NIH from 2007 to now, which moved us into the field of special antigen production, iPS using Bacmam systems, viral packaging services, and hopefully more advanced antibodies in the pipeline.
The link to the full NIH announcement is here.
To read more blogs on SBIR related topics, click here.
The current topics of SHIFT SBIR solicitation is listed below for Allele Blog viewers’ convenience:
• Applying opportunities in genomics and other high throughput technologies to understand fundamental biology, and to uncover the causes of specific diseases
• Translating basic science discoveries into new and better treatments
• Development of diagnostics, preventative strategies and therapeutic tools
• Development and clinical evaluation of biomarkers for alcohol exposure and alcohol-induced tissue injury
• Therapeutic development for alcoholism treatment
• Diagnostic assessment and treatment of alcohol use disorders and comorbidity
• Alcohol biosensors and data analysis systems
• Prevention, diagnosis, and treatment of fetal alcohol spectrum disorder and alcohol-related birth defects
• Minimal dose post-exposure vaccine for rabies
• Immunotherapy to kill HIV-infected cells
• Asthma therapeutic vaccine
• Novel antifibrotic therapies for progressive liver failure
• Diagnostic measurement devices or methods for assessment of urinary leakage and incontinence
• Therapeutics for diabetic wound healing
• Pediatric formulations
• Robust diagnostic biosensors for infants
• mHealth tools for assessing and addressing health in children and families
• Wearable diagnostic and therapeutic devices for physiologic monitoring and interventions
• Wearable biosensors for persons with genetic sensitivity to environmental factors
• Therapeutic interventions for persons with physical and developmental disabilities
• Advancement of novel botanical therapies for effective symptom management of non-life-threatening conditions
• Development of interactive technologies to improve and expand delivery of mind/body interventions
• Discovery of improved methodology for the characterization of plants and their secondary metabolites
• Development of standardized, objective methods to assess patient adherence to specific CAM treatment interventions;
• Development of devices/tools to assess consistency and fidelity of practitioner approaches and other aspects of protocol implementation
• Virtual settings or online tools for clinician training and implementation of fidelity monitors
• Development and validation of enhanced patient-reported outcome assessment tools for CAM (e.g. new user (clinician, researcher, and/or patient/study volunteer)–friendly interfaces, methods to improve compatibility with research and health informatics systems currently in use)
• Development of measurement tools for assessing expectancy for effects of CAM mind-body medicine, acupuncture, and manual therapy interventions
• Novel technologies that enhance/track/monitor “real time” adherence to drug abuse (and HIV+) treatment regimens
• Technology to improve the efficacy of substance abuse treatment, treatment adherence, and reduce recidivism among criminally-involved patients
• Mobile and/or internet technology based treatment interventions to augment traditional substance use disorder (SUD) treatments and their outcome
• Technologies and/or devices to boost medication adherence for SUD patients
• Technology-based treatment platforms to standardize interventions and to make them more community-friendly
• Integrate item response theory and computer adaptive testing in measures of addiction liability.
• Brief screening tools to assess relapse risks in and out drug treatment settings
• Use of the internet to link community based outreach and HIV testing services to facilitate access by drug users and their sex partners in neighborhood settings.
• Development of novel therapeutics, diagnostics, and devices for treating heart, lung, blood and sleep diseases and disorders
• New or improved measures, analytical methods, and instruments for gene expression in individuals with heart, lung, blood, and sleep disorders and diseases
• Health-care systems and outcomes research, including development of new quality measures for evidence-based heart, lung, blood, and sleep health care
• Models of behavior modification and other approaches to behavior change related to heart, lung, blood, and sleep diseases and disorders
• Devices and technologies to prevent cardiac ischemia/reperfusion injury
• Vaccines for the prevention or treatment of heart, lung, and blood diseases
• Non-invasive methods to diagnose DVT and PE
• Technologies and strategies to advance cellular therapies for heart, lung and non-malignant blood diseases
• Therapies to treat hematologic diseases and cytopenic states
• Technologies for in vitro reduction, inactivation or removal of microorganisms and other infectious moieties from blood, blood components, and plasma derivatives
• Development of products, technologies and services to diagnose, treat and/or prevent skin and rheumatic diseases, muscle disorders, and joint and bone diseases
Since signing into law in February, the American Recovery and Reinvestment Act of 2009’s ~10 billion dollar extra funding to the National Institutes of Health has resulted in funding 2,346 projects (or as supplements) so far. There have been several rounds of additional grant applications including the “Challenge” and the “Grant Opportunity” or GO grants, the funding of which will start in the fall. So, if you think you are seeing the leaves on the tree moving, maybe there is a breeze. Better proof for improvement, at least of the mood, of course would be the fact that your PI’s less stiff-looking face when you put in a request for purchasing reagents.
Buzz has it that right now is the hardest time for a postpoc to move on, even though it does not feel that great staying beyond a typical few years in the current lab either. Remember, job market recovery is a delayed action part of any economic recovery. So hold on tight and look ahead.
Companies in the research supply industry, large or small, are inevitably suffering along side with academic labs as well as the drug-aiming biotech industry and R&D centers of pharmaceuticals. Invitrogen (Life Technologies) let go of people in several rounds already. Specialty companies like Glen Research, leading supplier of oligo chemicals, are also shedding employees, it seems. Allele Biotech has not and is not planning to lay off team members, but we have not been able to replace people who recently left or support part-time employees’ level of work as we wanted to.
The ARRA stimulus money through NIH will be a main life line for many of us doing biomedical research in the next few months to a couple of years, depending on how Wall Street and the capital market shape up. The number of grants and total dollars will increase, however slowly it feels. No time to pop the cord yet but at least you can plan on doing that next experiment to get the paper published sooner rather than later, perhaps buying your genotyping kits and miniprep columns from us!
Don’t overlook the deep meaning of Independence Day. Enjoy the day and celebrate our freedom. Happy Independence Day.
The following information is courtesy of Rick Shindell
at SBIR Gateway, we post this excerpt to here to help more people who may be concerned to become aware of the situation.
The four House bills were marked up and approved on June 11, 2009 by the House Small Business Committee’s Subcommittee on Contracting and Technology and should go to the full SBC committee next week. The Senate bill is scheduled for markup June 18, 2009.
SENATE SBIR/STTR REAUTHORIZATION BILL S.1233 The Senate’s SBIR reauthorization bill was introduced June 10, 2009 and sponsored by SBE committee chair, Mary Landrieu (D-LA), and ranking member Olympia Snowe (R-ME).
At the time of this writing the bill was not yet available from the government printing office, so we can’t give you a link to it. We can provide you with an overview. It is close to but not exactly the same as last year.
Important points include:
* Extension of termination dates – 2023 (14 years)
* Improvements to strengthening the SBA Office of Technology
* Increase SBIR allocation by 0.1% per year (starting in FY-2011) until reaching 3.5% in FY-2020
* Increase STTR allocation to .4% for FY-2011; .5% for FY-2013; 0.6% for FY-2015
* Increase SBIR/STTR award levels to $150k phase I and $1M for phase II
* Awards shall not exceed 50% above recommended award levels
* Elimination of Phase II “invitation” process (i.e., DoD)
* VC small biz eligibility compromise limited to 18% of NIH SBIR Award funding, 8% at the other 10 agencies
* Allow small business to partner with federal labs or FFRDC without requiring a wavier from SBA
* Reinstate State and Rural outreach programs
* SBIR STEM Workforce Development Grant Pilot Program
* Continuation of Commercialization Pilot Program (DoD)
* Establish Commercialization Pilot Program for civilian agencies
* Nanotechnology Initiative
* Accelerating Cures – NIH Pilot
* Accuracy In Funding Base Calculations (keep em honest in the 2.5% extramural calculations)
* Increase in technical assistance from $4k to $5k
* SBIR and STTR Special Acquisition Preference
It is highly recommended that if you like the basis of this bill, contact your Senators and ask them to cosponsor this legislation, (S.1233 – A bill to reauthorize and improve the SBIR and STTR programs and for other purposes). This is very important if you want the Senate version to stand a chance on passing.
A tidbit you might have already known, the Challenge Grant through NIH’s ARRA stimulus program received 20k applications for some 200 to 400 awards.
The NIH stimulus grants do not have the SBIR obligations by a last minute change. How may all these affect Allele’s operations? We have submitted 3 grants to the NIH in the last 3 months, with total 4 now pending. It means that we sure are interested in NIH funding, which was, after all, how our company was started. On the other hand, we are also glad that we do have ongoing sales and services that link us directly to users of our technologies. In the current difficult economy and tight funding environment, we strive to be a company that supplies most essential biological research tools that could save average labs some 20-50% cost per item compared to buying from companies like Life Technologies and Clontech, etc. At the same time, we want to provide the convenience to our customers by covering a sufficient number of common reagent areas, a value small specialty companies normally do not offer. See our next blog for more comments on being a flexible and able provider of everything essential.
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