Jumping For Joy? Gene Therapy shows promise in Osteoarthritis

As regular readers of SRxA’s Word on Health know, your blogger is one of the estimated 34 million US adults who suffer from osteoarthritis.  The disease, the most common form of arthritis, is characterized by degeneration of cartilage and its underlying bone within a joint as well as bony overgrowth. The breakdown of these tissues eventually leads to pain and joint stiffness. Disease onset is gradual and usually begins after the age of 40, although in some people, myself included, signs and symptoms can appear in your teens or twenties, usually as a result of the wear and tear of repeated sports injuries.

The joints most commonly affected are the knees, hips, hands and spine.

The specific causes of osteoarthritis are unknown, but are believed to be a result of both mechanical and molecular events in the affected joint. Treatment focuses on relieving symptoms and improving function, and can include a combination physical therapy, weight control, medications and joint replacement surgery. But there is currently no cure.

So we were very interested to hear of a new study in mice in which researchers used gene therapy to reduce the risk of osteoarthritis.

And while there’s no way to know if the gene therapy treatment will help humans, or what the treatment’s side effects and costs might be, the findings are more than just good news for mice with creaky joints.

“This work identifies an approach that can make a difference,” explained study co-author Brendan Lee MD, PhD, director of the Rolanette and Berdon Lawrence Bone Disease Program of Texas. “There’s a great need for treating and preventing osteoarthritis.”

His study examined a protein that appears to be crucial to the lubrication of joints.  Researchers injected a gene related to the protein into mice and found that not only did the rodents begin producing it themselves, they also appeared to be resistant to joint and cartilage damage resulting from injury and aging.

Still, before our creaky knees start jumping for joy, as with all early research, there are caveats.

The research was in mice, not humans; the next step is to test the approach in horses, whose joints are similar to those of people. And the gene therapy doesn’t seem to do anything for damage that’s already occurred.

“This kind of therapy would probably not be very useful in patients who have advanced disease,” Lee said, adding that the treatment would likely have to be used with other strategies.

Dr. Joanne Jordan, director of the Thurston Arthritis Research Center at the University of North Carolina at Chapel Hill, said the findings “would be really very exciting if this translates up into humans.” The study, she said, appears to be reasonable and especially strong because it looks at osteoarthritis in the mice from different angles.

We agree. Any research that provides insight into the mechanisms of osteoarthritis development and a potential protective approach to its treatment are very exciting indeed.  A future with no more horse pills sounds good!

Be Still My Beating Heart! – Monty Python and the Holy Grail

Look up the term myocardial infarction (MI) in any medical dictionary and the definition will be something along the lines of –  the changes to the myocardium (heart muscle) that occur due to the sudden deprivation of circulating blood. The main change being necrosis, or death of myocardial tissue. Death of myocardial tissue.  As in dead, as in non-viable, as in beyond repair. Kind of reminds me of the infamous Monty Python Dead Parrot sketch… “Passed on! No more! Ceased to be! Expired and gone to meet ‘is maker!”….but I digress.

Fast forward from the British humor of December 1969 to an astonishing paper presented in Britain in April 2012  at the Frontiers in CardioVascular Biology meeting. In a keynote lecture, Dr Deepak Srivastava outlined results that have been described as a “game changer” with the potential to revolutionize the treatment of MI.   Srivastava used viral vectors to deliver genes directly into the hearts of adult mice that had experienced an MI. In his original “proof of principle” study, Srivastava was able to show that all that was needed for the direct  reprogramming of fibroblasts (a major component of scar tissue) into myocytes (the heart muscle cells responsible for  beating)  was the delivery of three genes.  The work , which took place in a Petri dish, was considered groundbreaking since it showed for the first time that unrelated adult cells could be reprogrammed from one cell type to another without having to go all the way back to a stem cell state. “Our ultimate hope is that, during the acute period following MI, patients will be able to receive direct injections of factors that transform the existing fibroblast cells in the “scar” into new myocytes. The resulting increase in muscle mass should help MI survivors to live more normal lives,” explained Srivastava.

Healthy heart tissue is composed of a mixture of several kinds of cells, including cardiomyocytes, which provide beating muscle and cardiac fibroblasts that provide architectural support to the myocytes. “When heart muscle cells become injured and die following an MI, patients have the major problem that these cells have little or no capacity for regeneration,” says Srivastava.  Part of the process of remodelling that occurs following the injury is that fibroblast cells migrate to the site and create the scar. At first, the process can be considered beneficial since without fibroblasts adding structural support damaged hearts would rupture. But later, difficulties arise when the fibrotic scar doesn’t contract like the muscle it has replaced. “Reduced global contractility means the heart has to work much harder, and the extra stress can ultimately lead to heart failure and even death,” said Srivastava.

One of the Holy Grails of cardiovascular research has been to replace these lost myocytes and return functionality to the heart.  Some of the first approaches to be investigated were the introduction of stem or progenitor cells to the sites of injury.  But many hurdles have been encountered including getting cells to integrate with neighboring cells in the heart, and there have been concerns that residual “rogue” cells could persist with the potential to keep dividing and give rise to tumors.

Srivastava, a pediatric cardiologist, explained how he got ahead of the game by “leveraging” knowledge from his work in embryo hearts. Over the past 15 years the focus of Srivastava’s lab has been to identify genetic factors responsible for the formation of embryonic hearts. From this work, his team identified 14 key genes that they felt were the major “on/off” switches for cardiac genetic programming. In this original study they were able to whittle things down to the three factors that were indispensible. The team then injected fibroblasts that had the three genes inserted directly into the scar tissue of mice.  They were able to show the fibroblasts differentiated into cardiomyocyte-like cells. In the latest study  they were able to take the process one step further by injecting a viral vector encoding the  3 genes directly into the scar tissue of mice who had just experienced an MI. “With these studies we’ve obtained even better results showing that the fibroblasts become more like cardiomyocytes and functionally couple with their neighbors. They could beat in synchrony and improve the function of the heart,” said Srivastava.

The next step will be to test the direct injection approach in a larger animal, such as a pig, whose heart is similar in size to a human.  But a big question remains “will the same combination of genes work in human hearts?” SRxA’s Word on Health will be watching and waiting. In the meantime…it’s back to Monty Python!

A Very Happy Christmas for Patients with Christmas Disease

SRxA’s Word on Health couldn’t resist this story. Not only did it provide us with a seasonal healthcare title but it allowed me to blog about a condition that I have been passionate about for most of my life. As a college student, one of my friends and mentors had hemophilia. He taught me a lot about the disease, about courage and dignity and hope and despair. His death from AIDS left me saddened but determined to pursue a career in healthcare. A few years later I had the opportunity to head up a hemophilia research project in the UK. One thing led to another and I spent the next 20 years of my life involved with transfusion medicine and blood products therapies. Although I’m no longer working directly in that field, later today, I will be running a training course on hemophilia.  I guess you could say it’s in my blood!

For those of you wondering what the above recollections have to do with Christmas Disease, let me explain.

Hemophilia B, a deficiency of coagulation factor IX (FIX) is also known as Christmas disease. Hemophilia is an inherited, potentially life-threatening disorder affecting an estimated 20,000 Americans, almost all of them males. Their blood doesn’t clot properly because of a faulty gene. In severe cases, they can spontaneously start bleeding . Internal bleeding in the joints leads to debilitating movement problems and intense pain.

Unlike most diseases that were named after the doctor that discovered them, hemophilia B is rather special because it was named for the first patient described to have it. Stephen Christmas was born in London, UK in 1947.  He emigrated to Canada at a young age and was diagnosed with hemophilia at age two by Toronto’s Hospital for Sick Children. The family returned to London in December 1952 to visit relatives and, during the trip, young Stephen was admitted to hospital. A sample of his blood was sent to the Oxford Hemophilia Centre where it was discovered that he was not deficient in Factor VIII, which is normally decreased in classic hemophilia A, but a different protein, which received the name Christmas factor in his honor (and later Factor IX).

Now, almost 60 years later, scientists have described the first unequivocal evidence of successful gene therapy for hemophilia. Past gene therapy experiments improved blood-clotting for only a few weeks.

This week, the New England Journal of Medicine reports that a single intravenous injection of an adenovirus-associated virus (AAV) vector that expresses FIX  was successfully used to treat 6 patients  with hemophilia B for more than a year. This is a remarkable breakthrough, given that patients normally need to infuse FIX two or more times every week.

The six men each got a single, 20-minute infusion of AAV. Each saw the amount of clotting proteins in their blood increase from less than 1% of normal levels to at least 2%, and in one case as much as 11%.  Although that may not seem like a lot, it was enough to allow all the men to cut back on the number of regular FIX treatments, and four stopped conventional treatment altogether.

Because their prophylactic use of factor concentrate was either eliminated or reduced, dramatic cost savings were achieved. In the United States, annual costs for a single adult patient with hemophilia B are approximately $300,000. Over a lifetime this adds up to a staggering $20 million. Whereas, the AAV is estimated to cost $30,000 per patient

An editorial that accompanied the study asked: Should the practicing hematologist rush to order this gene therapy vector if it is approved by the Food and Drug Administration?

Their answer – “probably yes!”  Still, they caution that the risks of this procedure are not yet totally clear. In one patient, liver enzyme levels were found to be about five times the upper limit of normal 2 months after gene therapy.

Nevertheless this gene therapy trial for hemophilia B is truly a landmark study, since it is the first to achieve long-term expression of a blood protein at therapeutically relevant levels. If further studies determine that this approach is safe, it may not only replace the cumbersome and expensive protein therapy currently used for patients with hemophilia B, but also translate into applications for other disorders, such as alpha₁-antitrypsin deficiency, and hyperlipidemias.

Now, that really would be a Christmas gift.

High hopes for long-term hemophilia B therapy

Investigators from St Jude Children’s Research Hospital and University College London recently announced extremely encouraging preliminary results of a Phase I/II gene therapy trial in patients with hemophilia B.

Hemophilia B, is a deficiency of Factor IX (FIX), one of the proteins necessary for normal clot formation. The disease affects about 1 in 30,000 people.  Without treatment, people with hemophilia B are at risk for uncontrolled, disabling and potentially fatal episodes of both internal and external bleeding.

The FIX gene is carried recessively on the X chromosome, and as a result the disorder, just like hemophilia A (FVIII deficiency), is almost exclusively seen in males, though it is carried by females.  Patients with severe hemophilia B, must normally inject themselves intravenously with FIX twice a week.

For such patients, gene therapy offers the enticing prospect of a near normal life, but previous studies have yielded disappointing results.

This study, presented last week at the American Society of Hematology annual meeting, was designed primarily to evaluate the toxicological safety study of low and intermediate doses. Because of the low dose used, researchers anticipated that trial subjects would produce little or no detectable FIX. So it was something of a positive surprise when the first patients FIX levels rose from <1% to 2% of normal, after infusion of the experimental vector.

While this rise, may not sound all that impressive, for a person with hemophilia it means the difference between severe and moderate disease.

Even more surprisingly, the patient’s FIX production remains elevated more than nine months later. Since the infusion the patient has also not suffered any spontaneous joint bleeds or needed prophylactic treatment.

Work on the vector began more than 10 years ago. An adeno-associated virus (AAV) vector known as AAV8 was picked because the incidence of natural infection with AAV8 is low and, like although it targets liver cells it does not integrate into the patient’s DNA. Participants received no immune suppressing drugs prior to infusion of the experimental vector.  The results so far suggest the experimental vector does not trigger the T-cell mediated immune response seen in a previous hemophilia B gene therapy trial.

The highest dose of the novel gene-vector combination is scheduled to be infused into the fifth and sixth study participants by mid-January. Investigators will then decide whether to expand the trial to include four more adults with severe hemophilia B.

As always SRxA’s Word on Health will be watching closely and will bring you news of further developments as they are announced.