Professor innovates gene therapy

TGRx provides jobs, brings revenue

J.J. Alcantara

Issue date: 3/25/08 Section: News

Richard Cooper, veterinary science professor, is leading students and professionals to research and develop treatments for certain genetic diseases.

Cooper, TransGenRx executive vice president of research and development, expands and enhances the way gene therapy works.

Gene therapy is used to treat individuals with single-disorder genes such as cystic fibrosis, sickle-cell anemia and certain types of diabetes.

Cooper said his technology has made gene therapy more efficient than previous methods.

“Every gene therapy trial that’s been started has been shut down because people are dying because they use viruses to transfer the genes,” said Bill Fioretti, co-founder and president of TGRx. “Those viruses have a habit of integrating to cancer-causing genes, if they integrate at all.”

Fioretti said TGRx’s gene therapy is different because Cooper’s technology has the ability to know which specific genes to change and will not cause cancer if it fails.

“[It does] it at a rate … of 100 more times efficient than traditional gene transfer technologies,” Fioretti said. “You know where it’s going to integrate and it does not cause cancer.”

Fioretti said the TGRx is the only company using this form of gene therapy because the technology is patented.

Fioretti co-founded TGRx in 2002 to license Cooper’s technology but the University also benefits.

Cooper said the University owns shares of the company and has a royalty agreement with TGRx.

“Both the AgCenter and the main campus are in the top-tier of royalty-producing income,” Fioretti said.

He said TGRx’s technology helps increase the University’s revenue because they own part of the license.

TGRx also produces protein drugs such as insulin and growth hormones for 10-20 times cheaper than the current costs using Cooper’s technology.

Cooper said TGRx uses chickens and chicken eggs to develop the protein.

He said TGRx engineers chickens to produce human proteins in their eggs.

Fioretti said TGRx’s first commercial product is a derivative of a human growth hormone.

“We will be making intermediate pharmaceutical ingredients,” Fioretti said. “We will sell that to someone who further processes it and sells it.”

TGRx partnered with the University and the AgCenter to develop this technology.

Fioretti said this partnership allows the company and the University to benefit.

He said TGRx first looks to the University before they advertise elsewhere to find graduates to work for the company.

Today, Fioretti said TGRx employs about 10 scientists who graduated from the University and about 12 student workers.

“Most [graduates] come out of biological sciences,” Cooper said. “But we’ve had a few come out animal sciences with an emphasis in poultry.”

Fioretti said as the company continues to expand, he will broaden his search for business, accounting and management graduates.

“We want to give graduates that are getting degrees in areas like molecular biology and biochemistry a place to work when they stay here,” Cooper said.

Fioretti said his long-term goal is to establish TGRx as an anchor for a viable biotech industry in Louisiana - specifically around Baton Rouge.

He said TGRx will attract support services and businesses like companies that raise poultry and purify and finish protein drugs.

“As we grow, there’ll be not just the jobs that we can provide,” Fioretti said. “Other companies that move in to provide services for us will be hiring people as we go.”

Fioretti said another goal of TGRx is to be a large-scale contract manufacturer.

“The companies that we partner with would have an interest to putting small- to medium-sized operations down here,” Fioretti said. “The whole thing goes toward not just attracting or keeping students and graduates in the state but bringing companies that will bring their workforce with them as well.”

Fioretti said this goal will help the biotech industry grow faster in Louisiana.

TGRx is currently located at the Wilson Laboratories but will soon move to the Louisiana Emerging Technology Center.

Fioretti said once the move to LETC is complete, TGRx will be able to increase their workforce.

“It’s really good for our company to have that kind of opportunity to expand in size and bring everybody together,” Fioretti said. “There’s something to be said about working in contact with all your peers and exchang[ing] ideas.”

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Contact J.J. Alcantara at jalcantara@lsureveille.com

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Way to target genes devised for gene therapy

Way to target genes devised for gene therapy

By Roger Highfield, Science Editor
Last Updated: 10:01pm GMT 17/03/2008

A way to carry out genetic surgery has been devised by a British Nobel prizewinner that is already under test on diabetic patients and being readied for use to treat Aids, blocked blood vessels and chronic pain.

So called gene therapy was hailed as a medical revolution two decades ago but progress has been slow, the successes have been hard to come by, and there have been a few deaths.

One key problem is that it has been hard to control where newly introduced genes end up in the genetic makeup of the patient - one fear is that they damage existing genes, or the way they are used.
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Now Sir Aaron Klug, a Nobel laureate working at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, has developed a more efficient way to target genes, so gene therapy can be done with surgical precision.

His team reports a new application of the gene fingers in the Proceedings of the National Academy of Sciences that it has have modified a piece of natural cellular machinery called “zinc fingers”.

These are zinc-containing proteins that bind to DNA and control how the genetic code - and the genes it contains - are read in our cells, so that a liver cell is different from a brain cell.

They have devised synthetic versions, called zinc-fingered nucleases, which have the capacity to recognise specific sequences of DNA which makes them extremely good at latching on to a specific spot, targeting particular genes without affecting others, so they can carry out genetic surgery to knock out genes or introduce new ones.

The new method is already being tested on more than 100 young diabetic patients who have lost sensation, a common complication, by the Californian company Sangamo BioSciences, after encouraging results in preliminary tests of the method to introduce a gene encoding a growth factor that can help restore sensation.

The work, backed by the Juvenile Diabetes Research Foundation, will be extended to see if it can help treat spinal injury.

Animal trials are already under way to use the same targetted gene therapy to reduce chronic pain and to knock out a gene called CCR5, the docking point used by the Human Immunodeficiency Virus to invade white blood cells, called T-cells, in AIDS patients, leading to a supply of non-infectable T-cells, which will combat HIV and the other infections which occur in AIDS patients.

Clinical trials are also in progress for stimulating the growth of new arteries in patients suffering from obstruction of the blood vessels in the limbs, which can lead to gangrene and amputations.

The new study shows they are effective at knocking out harmful genes too, also a fundamental tool for animal research to work out what genes do.

Sir Aaron explains: “The beauty of zinc-finger nucleases lies in their simplicity. Where other methods are long, arduous and often messy, it is relatively easy to switch off genes using this method.

“The zinc-finger design allows us to target a single gene, while the nuclease disrupts the gene. The single step process is extremely quick and reliable and opens up exciting possibilities for research and gene therapy.”

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Genetic screening raises tough ethical issues

Although this story was written about CF, the controversy  could just as easily have been written about SCID

Genetic screening raises tough ethical issues

Monday, March 10, 2008

BY CAROL ANN CAMPBELL

Star-Ledger Staff

The number of babies born with cystic fibrosis declined by half in Massachusetts after genetic screening started to identify carriers of the gene, suggesting similar declines may be happening across the nation, according to a recent report in the New England Journal of Medicine.

The Massachusetts study is among the first to examine the implications of widespread genetic screening, which is expected to increase as scientists discover genes for other genetic disorders.

Researchers say they cannot definitively explain the decline, but they surmise that couples who learn both carry the CF gene may decide not to have children, may turn to donor sperm or eggs or may test embryos before they are implanted in the womb. Also, pregnant women who learn they are CF carriers may test the fetus and have abortions if the test is positive.

“We think genetic screening has impacted the number of babies born with this disease,” said Richard Parad, an author of the brief journal report and a physician at Children’s Hospital Boston.

The study by the New England Newborn Screening Program, at the University of Massachusetts Medical School, looked at the number of babies born with CF — a serious genetic disorder that affects the lungs and digestive system — before and after 2002. That’s when the National Institutes of Health and the American College of Obstetrics and Gynecology recommended nationwide prenatal screening to identify carriers of CF.

The simple blood test, which costs around $100 to $200, determines if a person is a carrier of the CF gene. One out of every 29 Caucasians and one out of every 65 African Americans are carriers. If both parents are carriers, each child has a one in four chance of having CF. About 1 in 3,000 babies are born each year with the disease.

The Massachusetts researchers compared the four-year periods before and after 2002 and found the number of infants with CF dropped by 50 percent after the new screening recommendation. For each year after genetic screening became more widespread, the number of CF babies dropped from about 25-30 to 15 annually. In addition, among babies born with CF, far fewer than expected had the gene mutation associated with the most severe form of the disease.

Parad said scientists should examine the repercussions of recommending that four million women each year be tested for the CF gene.

“I think you might want to see what happens when you do that kind of widespread testing,” he said. “What do people do with this information?”

TROUBLING QUESTIONS

Genetic screening for CF presents unique ethical questions, particularly since many people with the disease live into adulthood. “There is a tendency to act as if genetic testing is about choice and information, and not really make the connection to the consequences,” said Arthur Kaplan, director of the Center for Bioethics at the University of Pennsylvania. “I believe the reason we pay for genetic testing is partly we know people will make reproductive decisions that will lead to less prevalence of the disease.”

Kaplan said the ethical questions will become more complex as genetic screening expands.

“What if there was a test for homosexuality? Or short stature?” he asked.

In cystic fibrosis, pancreatic, intestinal and lung secretions tend to be thick, clogging organs, especially the lungs. Complications can include lung collapse, heart failure and liver damage. In the past 25 years, medical advances have doubled the average life expectancy for people with CF, according to the Cystic Fibrosis Foundation, a national organization. Life expectancy is now 37.

The organization, in a statement, called genetic testing a personal matter and said it is too early to know if the Massachusetts decline is being duplicated in other parts of the country.

Preston W. Campbell III, the foundation’s executive vice president for medical affairs, said prospective parents should know that promising drugs are in the pipeline.

“Most babies born today with cystic fibrosis will live long and full lives,” he said.

Parents involved with the New Jersey State Organization of Cystic Fibrosis said they understand the joys and frustration of raising CF children.

Bob Frees of Linden has five children, two with CF, including a 26-year-old daughter who recently underwent a double lung transplant. Frees said he and his wife are happy genetic testing was not available when his children were born.

“We would not want to have to go through those difficult decisions,” he said.

In contrast, Frees said his married son with CF fears passing the disease on to his children and wants testing.

“He doesn’t want to see a child suffer they way he has suffered,” Frees said.

Another parent, Beth Maisto of Little Egg Harbor, has three children — two with CF. She did not learn she and her husband were carriers of the gene until she was tested during her third pregnancy. The knowledge led doctors to test her older son, who had frequent respiratory problems; they found he had CF. “They sent us to counseling and asked if I wanted to terminate the pregnancy,” she said. “But I couldn’t do it.”

Life with Michael, 7, and Julie, 4, can be difficult. Each is on multiple medications. She and her husband work opposite shifts to care for their children.

“The unknown is scary,” Maisto said. “But when you have an actual child in your arms, you see it’s not that bad. My kids are the best thing in my life.”

Carol Ann Campbell may be reached at ccampbell@starledger.com.

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Cord Blood Stem Cells Give Life

Cord Blood Stem Cells Give Life

A medical option that’s now available

Rumbo, News Feature, Liliana Cadavid, Posted: Feb 24, 2008

Editor’s Note: Umbilical cord blood is gaining acceptance as a source for transplant stem cells to save babies with Leukemia and adults who cannot find matching bone marrow traits. Although this practice is considered controversial in certain medical and parenting circles, its successes have proliferated a number of cord blood banks nationwide. Liliana Cadavid, a Fellow of the DNA Ethnic Media Fellowship sponsored New America Media and SoundVision Productions, is a health reporter. She wrote this story for Rumbo, a Spanish-language publication based in San Antonio, Texas.

Cord Blood Stem Cells treatments are a feasible, accessible and increasingly available option in modern medicine that helps to save hundreds of lives. Camilla Alecia Diaz-Weber, 2 years old, had a big smile when she came in to the transplant clinic at the Methodist Hospital in San Antonio for her monthly check up.

She moved her little arms hurriedly, excited to see the clinic staff. Everybody was very familiar for her. She has been there many times after the cord blood stem cells (CBSC) transplant that she received four months ago.

When Camilla, from Eagle Pass, Texas, was 19 months old, she was diagnosed with severe combined immunodeficiency (SCID), a rare genetic disease that according to the National Human Genome Research Institute (NHGRI) affects 40 to 100 children in the United States each year.

Children with SCID are very susceptible to any type of infection because they lack an immune system, according to hematologist Jaime Estrada, member of the Transplant Program at the Texas Transplant Institute in San Antonio (TTI). “The only treatment that can cure these children is the bone marrow or cord blood stem cells transplant. If they are not treated the prognosis is fatal,” he said.

Stem Cells have the ability to develop into other types of cells with specific functions, explained hematologist Anthony Infante, professor of Immunology at the University of Texas Health Science Center in San Antonio. The blood from the umbilical cord, he added, is particularly rich in cells that have the ability to mature into others cells that form blood.

“Currently, CBSC are widely used to treat leukemia, diseases of the immune system and other inborn related disorders in children,” he said.

Camilla was fortunate. On July 14 2007, she received a transplant at the TTI, covered by her family’s private health insurer. The transplant saved her life.

“Her doctor told us that in about a year she should be totally cured,” said Lori Diaz Weber, Camilla’s mother.

Similarly to Camilla, Ithzbel Aurora Huerta, 3 years old, from Laredo, Texas, was treated with CBSC, was covered by Medicaid, but suffered from a different disease. When she was two months old, she was diagnosed with an inborn bone marrow failure known as Severe Aplastic Anemia and received the transplant. “If it had not been for the CBSC transplant, I would not have her with me today,” said Arizbel Perez, Ithzbel’s mother.

Arizbel said she never heard of treatment with CBSC, but now that she has learned about it, she tells all her girl friends if they decide to become mothers, they need to plan on donating their babies’ cord blood to a public bank. “Someone who did this at a certain moment, saved my daughter life,” she said.

The CBSC transplant has many advantages, according to Donna Wall, Director of the Bone Marrow and Cord Blood Stem Cells Children’s Transplant at TTI. The most important thing in a transplant, she explained, is to find a donor who is compatible and certainly one of the things that we like the most about CBSC is that we don’t have to find a donor that has exactly the same type of immune system.

Also, she added, it is easier to find a cord blood unit in a public bank than it is to find a live bone marrow donor. “When we perform transplants in children, the CBSC is our preferred source from an individual outside the family.”
But when it comes to treating adults, the CBSC might not always be so helpful.
The problem of CBSC transplants is that the cells that are available are the ones that were obtained at the baby’s delivery; there are no more, said Dr. Yago Nieto, professor of the Department of Stem Cells Transplant at MD Anderson in Houston.

“Sometimes, a unit of cord blood can be very small to treat an adult patient”, Yago said. “It can work well but we have to make sure that the number of cells will be enough according to the patient’s weight.”

Right now, scientists are studying an option to work in laboratories to expand the number of stem cells in a cord blood unit, said Infante, but “the idea is being able to do so without altering the stem cells’ ability to function properly.”

To Store or to donate- a dilemma
Is it better to pay for storing a cord blood unit of a newborn baby or to donate it to a public bank?

That’s a common question among mothers- to- be. It is also a frequent question that Dr. Donna Wall of the Texas Transplant Institute in San Antonio is asked by doctors, lawyers and moms. “Public Banks have an important purpose: provide units of CBSC to those that need them”.

The majority of people, she continued, are not going to ever need a transplant. “So, why pay to store a baby’s cord blood in order to use it for that same baby in the future, if that is not likely to happen”, she said. “On the other hand, many of the disorders we treat are inherited, so the blood is going to have the same problem.”

Doctor Yago Nieto, from MD Anderson in Houston, suggested that people should donate cord blood to a public bank. “Doing this causes no harm to health, it can help save lives and it does not cost anything. To store cord blood in a private bank will cost a lot”.

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Nine years after bone-marrow transplant, sister saves brother with liver donation

Nine years after bone-marrow transplant, sister saves brother with liver donation
By Yuval Azoulay

A 30-year-old woman donated her liver to her 9-year-old brother two weeks ago, saving his life for a second time since he was born.

Nine years ago, bone marrow from the sister was transplanted into her baby brother who was born suffering from Severe Combined Immunodeficiency, a genetic disorder that impairs the immune system.

At the time, doctors at the Sheba Medical Center, Tel Hashomer, believed that bone marrow from his sister would cure his illness and allow him to lead a normal life. Without hesitation, the sister gladly obliged to make the donation.

After the operation, the child grew up in good health. Three months ago, however, his situation suddenly deteriorated. Tests showed he was suffering from a very serious kidney disease that damaged his lungs. His breathing became labored, and the oxygen level in his blood was half its normal level in a healthy child.

“The disease was very serious, and there was no other option but to carry out a liver transplant,” said Dr. Yaron Avitzur, a specialist in children’s liver diseases at Petah Tikva’s Schneider Children’s Medical Center. “For three months, he lied here by an oxygen tank. Even with the tank, his oxygen levels were low and his physical functioning was very limited.”

Because of his perilous condition, doctors decided to transplant a liver, but worried that if the body rejected the organ, the side effects might further deteriorate his condition. While examining the boy’s medical history, doctors discovered that his sister’s liver would not be rejected because of her bone marrow donation nine years ago.

Quick decision

Now a mother of two, the sister had to reach a quick decision. By agreeing to donate the organ, she was exposing herself to a potentially life-threatening situation, doctors told her. Unlike donating bone marrow, removing a liver for donation was a complicated procedure.

“At the start I was terrified,” she said. “This wasn’t like donating bone marrow. In this instance, they make a cut in the body and remove an organ. After realizing that it would allow my brother to lead a normal life, I had no doubt I would go through with it. I consulted with the rebbetzin [the rabbi's wife] and received her blessing, and I entered the operation room as though I were walking into a hotel.”

After hours of operation, the liver was successfully transplanted.

“The liver is functioning in the boy’s body,” said a doctor who was part of the team that carried out the operation. “He will be let out of the emergency care ward next week and sent home. He no longer has to take medication against his body rejection the transplant, nor did he need such medication during the operation.”

Hospital officials said the transplant was a rare medical case almost without precedent in the annals of medical history. “This is a rare case, and we estimate that in the entire world only a few similar cases have occurred,” Dr. Avitzur said.

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Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency Diseases

Section IX: Severe Combined Immunodeficiency Diseases

Biology of Blood and Marrow Transplantation
Volume 14, Issue 1, Supplement 1, January 2008, Pages 73-80

Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency Diseases

Morton J. Cowan^{1, ,} , Benedicte Neven², M. Cavazanna-Calvo², A. Fischer² and Jennifer Puck^3
1Pediatric Blood and Marrow Transplant Division, UCSF Children’s Hospital, San Francisco, California
²Service d’Immuno-Hématologie pédiatrique, Hôpital Necker-Enfants-Malades and Laboratoire INSERM U768, Paris, France
³Division of Immunology, Department of Pediatrics, UCSF Children’s Hospital, San Francisco, California

Available online 24 December 2007.

Abstract

Hematopoietic stem cell transplantation (HSCT) is the only curative option for most children with severe combined immunodeficiency disease (SCID). Survival for SCID following HSCT has significantly improved over the past several decades, and ranges from 70% to 95% depending on the clinical condition of the child at the time of transplant, the availability of an HLA-matched sibling donor, and the SCID genotype/phenotype. In this article we will review the types of SCID and discuss the critical HSCT issues that confront us today, including the optimal source of donor cells when an HLA-matched sibling is not available, as well as the pros and cons of using conditioning therapy pretransplant. As SCID children have been followed for several decades, it is becoming apparent that long-term outcome and durable T and B cell immune reconstitution are quite variable depending on the initial treatment and source of donor cells. Finally, the development of methods to improve the early diagnosis of SCID along with designing prospective trials to evaluate the best approaches to curing these diseases with minimal toxicity are critical to improving outcomes for children with SCID.

Key Words: Severe combined immunodeficiency (SCID); Hematopoietic stem cell transplantation. Immune reconstitution; Newborn screening; Public health; Primary immunodeficiency; Genetic disease; Early diagnosis

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Rare Immune Disorder Disproportionately Affects American Indians

Thursday, December 20, 2007

Science & Medicine

Rare Immune Disorder Disproportionately Affects American Indians

The AP/Farmington Daily Times on Sunday examined SCID, an immune deficiency disorder prevalent among American Indian children. One in every 2,500 Navajo Indian children has the condition, compared with one in 100,000 children in the general population.

Researchers have isolated about 12 genes that are linked to SCID, and Navajos and Apaches are thought to have the most severe form of the condition, where they lack a certain gene. Without that gene, children with SCID are unable to repair DNA or develop T and B cells, which fight disease.

There is no standard test to detect SCID among children. Children with the condition usually will be diagnosed after having a persistent infection, generally within three months of birth. Jennifer Puck, who studies inherited immune deficiency disorders at the University of California-San Francisco, said she is working on a test that would determine whether a child is immune deficient.

Mortan Cowan, a physician who has worked with SCID patients for more than 20 years, said efforts are under way on reservations to educate doctors about signs of the condition (Fonseca, AP/Farmington Daily Times, 12/16).

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‘Baby in a bubble’ pioneer has leukaemia

Last Updated:4:26pm GMT 18/12/2007

A child undergoing pioneering gene therapy for what has become known as “baby in the bubble syndrome” has developed leukaemia.

Great Ormond Street Hospital has announced that the boy, who was born with no immune system, has developed the chronic bone marrow disease two years after successful treatment for X-SCID.

Affected children produce no lymphocytes and have no natural defence against infection, meaning they must be kept isolated from the outside world.

X-SCID affects only boys and is caused by a single faulty gene.

In the first trial of its kind in Britain, 10 babies with two types of potentially fatal immune system diseases were given the treatment.

Medics in the UK knew that there was a risk of the children developing leukaemia as a result of the treatment, but the boy, who is three years old, has been the first to do so.

A trial in France of a similar therapy was stopped in 2002 after four of eleven children developed leukaemia.

Professor Adrian Thrasher and Professor Bobby Gaspar, consultant immunologists on the gene therapy programme, said in a statement: “As with any medical treatment there are associated side-effects.

“The development of leukaemia is now a recognised side-effect in this study, though the risks are balanced by the severity of the condition and the lack of good alternative treatments for X-SCID.

“This first study is now closed to recruitment while safer improved formulations of the genetic medicine are being prepared for clinical trials next year at several centres including Great Ormond Street.”

They added: “Every child matters.

“Families are counselled very carefully before taking part in these treatments.

“Gene therapy appears to offer a less intrusive treatment for those patients without a good bone marrow donor and, if we continue to make advances, may become the treatment of choice.”

He added: “All patients are monitored carefully as part of their care plan.”

Affected children are likely to die within a year without a bone marrow transplant.

Gene therapy involves a working copy of the defective gene being placed in the child’s bone marrow cells and these are then returned to the child.

Great Ormond Street has been working with the regulator, the Gene Therapy Advisory Committee (GTAC), since the discovery of the boy’s condition at the end of last month.

Professor Martin Gore, GTAC chairman, said: “My sympathy goes out to the child who has developed leukaemia following gene therapy for X-linked SCID and their family.

“I also feel for the nurses, doctors and researchers in the gene therapy team at GOSH who are utterly dedicated to helping children with serious life-threatening diseases.

“They are a highly regarded and professional group who have counselled families extensively about the risks of gene therapy, including the possibility of the development of leukaemia.

“I know that this child is in good hands and that colleagues at GOSH are doing everything possible to treat this child’s leukaemia successfully.”

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