Transgenic animals

On the Horizon: HFA Part 1

Last week the bleeding disorders community met in Cleveland, Ohio at Hemophilia Federation of America‘s annual meeting. It was a fabulous time to meet with friends and colleagues, and to learn about new treatments in inhibitors, new drugs in the pipeline and about psychosocial issues. One of the best attended sessions was the one on gene therapy. Entitled “On the Horizon,” the session was a 90-minute review of new products coming our way, and an overview of gene therapy, how it works and who is working on it.
Dr. Sanjay Ahuja, medical director of Rainbow Children’s Hospital, first spoke about “New and Emerging Therapies.” Expression Therapeutics is working on “ET3i,” a recombinant
factor VIII (rFVIII), that should give a higher yield, with the focus on lower cost per unit.

Another interesting therapy is called “transgenic.” Pharming Group has found a way to derive transgenic rFVIII from the milk of rabbits. Ahuja explained that scientists have learned how to take a human gene that makes factor VIII, put in rabbits, and have factor expressed through their milk. This is called “lacto-recombinant factor.”

This generated laughs from the audience, and one man gestured like he was milking a cow. And while Ahuja joked that we could get our kids to drink more milk finally, the actual drug would not be in milk to drink, but commercially available as an infusion. It would be cheaper to produce, with a high yield, making factor much more affordable.

“New things and better things coming,” Ahuja said.
Many people in the audience already knew about the innovative therapy called emicizumab (commercial name: Hemlibra), a bispecific monoclonal antibody that mimics factor VIII by bringing together activated FIX and FX together, replacing the function of FVIIIa. It’s not a factor product! There was a brief discussion about the deaths associated with its use [see our upcoming article in PEN for a detailed discussion on these]. Bioverativ and Shire are also working on bispecific monoclonal antibody and Shire’s is actually a bi/trispecific. These drugs are called “FVIII-Mimetic.”
Another innovation for FIX is from Salk Institute/Arcturus Therapeutics, currently in pre-clinical studies. It’s not gene therapy, though it involves taking RNA to the liver to
make factor.
On the horizon for inhibitors are products in the FVII market. HEMA Biologics/LFB, are working on an activated FVII.  rEVO Biologics/LFB are working on FVIIa in transgenic rabbits.
Even a long acting, subcutaneous FVIIa is being made by Catalyst Biosciences and OPKP Health.
Perhaps the biggest surprise of all is rFVIII being made in lettuce at the University of Pennsylvania, and this you do eat!
Dr. Stacey Croteau, medical director Boston Children’s Hospital, and Associate Director of the Boston Hemophilia Center next spoke about gene therapy. She gave a brilliant overview, too detailed for here, but if you look at the slides, you’ll get a sense of just how much activity is underway. And all through the four-day conference, I kept hearing chapter leaders talking about not “if” gene therapy occurs, but “when.” More and more, it is becoming a reality.
Dr. Croteau first explained that there are three basic types of gene therapy:
1)   Direct therapy (injection into the patient)
2) Cell based (in which you take cells out, alter the genes, then reintroduce the altered cells to the individual, called ex vivo)
3)   gene editing (going directly into a defective gene to make it work)
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There was a good discussion of how adeno-associated viruses (AAV) are mostly used as the vehicles (vectors) to introduce the altered genes into the patient. Why a virus? They are good at replicating—viruses need to quickly replicate to infect the host and survive. But Dr. Croteau stressed that the AAV8 is stripped down and rendered harmless, so just the FIX gene is left. It’s then introduced back into the patient and goes to the liver (AAV vectors love the liver!), embeds into hepatocytes (liver cells), degrades and becomes part of that cell and starts to express normal coagulation factors into the bloodstream.
Dr. Croteau explained how difficult gene therapy is. You must get the gene delivered to the right cell type in sufficient quantities; then it must switch the gene on, all the time avoiding body’s natural immune response.
In 2011 there was the first successful AAV gene therapy for hemophilia B. With high doses, the patients in the clinical study had their factor levels go from severe to moderate and even to the mild range.
Not all gene therapy research is using AAV; there are all types of AAV vector subtypes. Looking at the slides, why so many? Not everyone will be eligible to use a particular vector. Just like with factor, one gene therapy won’t fit all. Dr. Croteau concluded that it’s good we have several options for gene therapy, and many look very promising!
To learn more about gene therapy trials, you can look at
And very honorably, the speakers reminded us that those patients who have volunteered and are volunteering for new therapies and gene therapy make it possible for the rest of us to enjoy a higher quality of life. Indeed, they are our heroes.
This was a great session to attend; thanks to Drs. Ahuja and Croteau for their presentations! Please read HemaBlog next Sunday when I’ll give an overview of the entire HFA meeting… which was fantastic!

Got Rabbits? Their Milk May Treat Inhibitors Someday

PEN has printed in the past articles about coming products, like long lasting and human-cell line products. We’ve also mentioned transgenic animals—which express proteins in their milk that can be used for human treatment of certain disorders. Hemophilia is one of the therapies being researched to create products from transgenic animals. 

Charlton [Massachusetts] farm to raise rabbits for medicine


A French biotechnology company that turns milk from genetically engineered goats into medicine plans to expand operations at its farm in Charlton by raising rabbits that produce a blood-clotting agent for patients with hemophilia.
LFB SA and its Framingham-based subsidiary rEVO Biologics plan to build a colony of 1,000 to 1,200 rabbits making a protein called Factor VIIa at the farm, said Dr. William Gavin, a veterinarian and senior vice president of operations for rEVO.

“We’re going to have the first shovel in the ground in August,” Dr. Gavin said. “About one year later we will be producing milk here from the rabbits that produce the Factor VII in their mammary glands.”

The plan represents the first potential product expansion at rEVO, previously known as GTC Biotherapeutics, since it launched a clot-busting drug called ATryn in 2009. ATryn was the world’s first drug made in the milk of genetically altered animals.

LFB has been producing limited amounts of Factor VIIa in the milk of rabbits in France while also testing the protein in humans. The company said Monday it expects to launch the third and final phase of human studies this year.

If approved, LFB would market its Factor VIIa product as a treatment for hemophilia A and B patients who have developed inhibitors, or antibodies, to other clotting proteins known as Factor VIII or Factor IX.

The global market for blood disorders, including hemophilia, is estimated to reach nearly $64.7 billion by 2017, according to analyst Usha Nagavarapu in a market research report published last year by BCC Research of Wellesley.

NovoSeven, a Factor VIIa product sold by Novo Nordisk of Denmark, posted worldwide sales of 8.9 billion kroners in 2012, or about $1.6 billion in current dollars.

Founded in 1993 as part of Genzyme Corp., rEVO has offices and laboratories in Framingham. The company developed transgenic animals as an alternative to traditional biologics manufacturing.

Transgenic animal production generally starts in a laboratory, where scientists inject human genes into an early animal embryo. The embryo then gets implanted in the womb of a surrogate mother. If the procedure is successful, the animal born will carry code for a human protein in its genes. Then the animal can be bred normally to produce offspring with the human code.

That is how rEVO built its herd of goats on its 383-acre Charlton farm. Transgenic females in the herd produce milk carrying antithrombin III, a protein involved in blood clotting. The company processes the milk to a sterile powder form of antithrombin III for sale.

Dr. Gavin said rEVO plans to bring transgenic New Zealand White rabbits from France to build a new Charlton colony. The company chose rabbits rather than goats to produce Factor VIIa because rabbits can produce the key protein with certain sugars needed for the best therapeutic results.

Rabbits can also produce 200 milliliters of milk per day, or nearly 7 ounces, and they lactate for about three weeks.

Contact Lisa Eckelbecker at Follow her on Twitter @LisaEckelbecker. 

So I just saw this in the newswires… and go here to read about my visit to this farm a few years ago, and to see pictures of the goats mentioned in the articles.
You can also learn more here:

Great Book I Just Read
Bonk: The Curious Coupling of Science and Sex [Kindle] 
by Mary Roach

This best selling author examines the history of the scientific study of
sex, and researches the sex researchers. It’s at once funny, interesting, witty
and head-scratching. From examining artificial insemination of sows in Denmark,
to examining her own physiological reactions in bed while participating in a
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spot on. Four out of five stars

From Humble Farm Animals

I’ve been to a lot of places recently, and one of the most interesting ones was the GTC Biotherapeutics farm in Charlton, Massachusetts, on Friday, May 21, to see transgenic goats.

I wrote about transgenic animals in the February issue of PEN, when I discussed hemophilia products that are being developed now. Factor produced through transgenic animals may one day become a source of factor concentrate. And if production proceeds as hoped, transgenic animals may represent a high volume and thus low-cost way to produce factor and other proteins.

What are transgenic animals? These are animals that have been genetically modified to express human therapeutic proteins in their milk. In other words, human factor can be collected by milking these animals. The source material is raw milk. And once the proteins are collected and purified, they can be used to treat diseases and genetic or metabolic disorders in humans.

Now, the goats located on the 167 acres that bridge the towns of Charlton and Spencer, Massachusetts, are not being raised to create factor, although factor IX is being produced by transgenic pigs in Virginia, and factor VII is being made by transgenic rabbits in France. The goats we visited express the protein used in ATryn®, a recombinant form of human antithrombin. Atryn® is the first transgenically produced therapeutic protein to receive FDA approval and the first recombinant antithrombin approved in the U.S. So as wild as this all sounds, GTC already has an FDA-approved, transgenically produced therapeutic in the marketplace. And GTC is hoping to initiate a clinical trial for their factor VIIa product later this year.

My husband Kevin and I requested a tour, and we were enthusiastically greeted by Ashley Lawton, Vice President, Business Development. Before we entered the building, we had to dip our shoes into a disinfectant solution, to kill any microbes. Of course, I was wearing sandals!

Safety was stressed at every part of the two-hour tour.

Ashley told us that the goats originated from New Zealand, because this is one of the few countries free of scrapie, a fatal and degenerative disease in sheep and goats. Why use goats and not cows? Goats produce more milk and their milk has a high protein content; they also have a four-month gestation period. And they are relatively easy to breed and maintain.

GTC is a pioneer in the field of transgenic technology, and because it involves making human therapeutic proteins, regulatory agencies want extensive documentation. Everything done to the animals, from having their hoofs cleaned to operations, is documented fully.
Dr. Bill Gavin, General Manager of Operations and chief veterinarian, joined our tour and told us, “Because we were a new technology… we were held to an even higher level of safety.”

We toured the labs where the genes are spliced into the embryos. We traveled to the barns where the goats are penned. Somehow I expected sterile, see-through cubes with goats hooked up to machines. Instead, we saw adorable goats comfy in stalls, much like you’d see on any farm. The “kids” were cuddled together. Young adults were able to mingle and hang together; they even had toys to play with like bouncing balls. Goats love to climb, and these had cubes to scale.

Goats are fascinating. They are curious, sociable and always hungry! They’ll nibble on anything and eat just about anything. I couldn’t go too near them but got close enough to see these are probably the best cared for goats on earth.

I’ve been invited to view the pigs in Virginia that are being researched currently to produce factor IX; after this trip I think I need to go check it out.

Actually seeing the goats and the technology made this seem more than just a pipedream. Perhaps the biggest revelation is that we would not “drink” the treatment, which I actually believed! Once the protein is purified from the milk, it will be freeze-dried and prepared as an injectible, biological product, very much like the factor concentrates available on the market today.

I know there are those in our community who might think this is unfeasible. But for me, this is a ray of hope. Transgenic animals might be particularly attractive as a way to treat hemophilia in developing countries, where there is great need for a low cost product, and plenty of it. Do you know which countries are the top five in population?

In order: China, India, US, Indonesia, Brazil. Four of the five most populated countries on earth are developing countries. So it stands to reason that a huge population of people with hemophilia are underserved and in need. This wonderful tour on a warm spring day left me hopeful that plentiful help for them might someday come from this fascinating new technology from humble farm animals.

Interesting Book I Just Read
The Seven Powers of Questions
By Dorothy Leeds

This book asks questions, actually: why do we talk so much and not listen? How can we better focus and learn? What are effective ways to ask questions? Leeds covers a lot of ground about how we communicate, mistakes we make in trying to form relationships (whether business or personal), and how to be a better listener. Asking questions makes us better listeners, helps us to focus, diffuse defensiveness in others, calms situations. She notes the things that make us poor listeners: having preconceived ideas, jumping to conclusions, being emotionally charged. Questions help break down those barriers, and make us more open to listen, and then to think. This book got off to a very weak start (I think it was opening with a not-so-good quote from the 1960s Star Trek TV show [and I consider myself a fan]) with a plethora of cliché quotations from oft-referenced works (Ask a better question to get a better answer: how many times have I heard that?) and also had a weak ending, by evolving into a “Where is your entire life going and how will you get motivated to be an empowered person and make your dreams come true…” But overall there is material that is vital to know and this book will be welcome to read if you are new to self-help books or any book on communication. Two stars.

Big Week for New Hemophilia Products

There was lots of news this week under the heading of “What can I look forward to when I don’t have gene therapy?”

How about extended half-life factor? So, instead of prophy three times a week, you dose once, and it lasts all week? Extended half-life factor is the next great thing in hemophilia, while we wait someday for a cure. I think this will be a reality in the next two years.

This week Biogen Idec (a company right here in Massachusetts; yes, they are freezing just like the rest of us this week) announced that they’ve dosed their first patient with extended half-life recombinant factor IX.There are about 6 companies studying long-acting factor IX. One of these is also GTC Biotherapeutics, also located in Massachusetts, which has a FIX product in preclinical studies. And this is really different: GTC is using transgenic animals, like rabbits and goats. These animals are specially bred to excrete human FVIII or IX through their milk glands. Fascinating!

Now even when a company has a new product in clinical trials, this doesn’t mean that it automatically will come to fruition. These are trials, and sometimes things don’t work out. For example, just this week Bayer cancelled its LipLong study, which seemed so promising. Bayer was exploring an extended half-life factor VIII (BAY 79-4980), but results weren’t as expected. But don’t worry; they are also working on another extended half-life FVIII in different preclinical trial.

One thing to note: you can actually voluteer to participate in one of these studies. Go to You could help make history!

Great Book I Just Read
Take Yourself to the Top by Laura Fortgang

I read this book every two years at New Year’s to get motivated, to reasses and to plan. Not only for my business, but also for myself. This book has been around a while, but I love its no-nonsense approach, its friendly and cajoling tone, its practical applications for thinking bigger, laying the groundwork for success and removing all obstacles. I recommend it for anyone starting a business or starting a new passion within a business. First step, get off the caffeine. Man, it’s like she reads my mind in this book at times! Four stars.

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