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Genetic Disease Research

Our researchers are developing pioneering therapies for genetic disease

Genetic diseases in children are rare, difficult to treat and often fatal. As a result, they have captured the attention of researchers at the University of Minnesota, which is on the leading edge of research to treat and eliminate some of these diseases. They are focusing on three groups of genetic diseases: Epidermolysis Bullosa; metabolic storage disorders,  and bone marrow failure syndromes/diseases.

Epidermolysis Bullosa

Children born with this disease are missing the vital enzyme called Collagen 7, which works like Velcro in between the skin’s layers. This condition causes horrific wounds, both external and internal.

While past treatments have focused on topical therapy, similar to that given to burn patients, by performing BMTs the patient’s body starts producing the Collagen 7 enzyme provided by the healthy donor’s bone marrow. In March 2010, the ninth patient was treated with umbilical cord blood from a non-related donor and mesenchymal stem cells to help heal the skin’s damage. The results from this patient may further improve the treatment of EB.

Metabolic storage disorders  

Inherited metabolic storage disorders are diseases in which the body lacks an enzyme, or protein, needed to metabolize a substance, causing the substance to build up in the body. When it does, it can create life-threatening problems. Children with metabolic diseases often have progressive brain and nerve deterioration involving the heart, bones, lungs, eyes, ears, nose or airway.

These diseases are degenerative, making early detection and intervention key to optimum outcomes. Stem cell transplant (BMT/UCBT) has been explored for many of these diseases as a means of providing a continuous source of the patient’s missing enzyme. The purpose is to arrest the course of the disease, saving the life of the patient and maintaining quality of life.

Adrenoleukodystrophy (ALD) 

ALD is a metabolic storage disorder that causes damage to the myelin sheath, the insulating membrane surrounding nerve cells in the brain. Sadly, by the time a child is diagnosed with ALD, he or she may already be experiencing considerable degeneration.

To calm the inflammation during the six weeks it takes to conduct a work-up leading to a BMT, physicians at the University of Minnesota, already a world leader in the treatment of ALD, plan to give mesenchymal stem cells intravenously.

They are also using high-dose anti-oxidant therapy administered intravenously to reduce inflammation from oxidative stress that often occurs after a transplant in children with advanced ALD.  This type of treatment may also be helpful for children undergoing cancer treatment who also experience oxidative stress.

Hurler Syndrome  

Children with Hurler syndrome often die before the age of 10, but not before they experience a variety of symptoms, including abnormal facial features, deafness, heart valve problems and a decline in neurocognitive development.

A BMT is the only proven therapy that can stabilize this decline, but the disease continues to progress for a year after transplant as it takes time for the healthy donor cells to start producing enough of the missing enzyme. University of Minnesota researchers have developed the only approved protocol to provide enzyme therapy through the spinal fluid up to 6 months after BMT, thus alleviating the continuing damage caused by Hurler’s Syndrome.

Dr. Jakub Tolar, Assistant Professor, Inherited Metabolic Storage Disorder program at the University of Minnesota, said, “The standard of care five years ago for Hurlers was transplant only. Now, it is combination therapy with transplant. Other diseases have moved to enzymes only. The advantage of the University of Minnesota is that everyone has a research mind and not just a practitioner’s mind.”

Fanconi Anemia

Fanconi anemia is an inherited condition leading to bone marrow failure, followed by acute myeloid leukemia in many young patients. Unlike what happens in other metabolic diseases, transplantation replaces defective bone marrow but does not cure the disease. Patients are still highly prone to cancers.

The University of Minnesota, which treats more patients with Fanconi anemia than all other U.S. hospitals combined, has pioneered the use of pre-implantation genetic diagnosis to create a healthy matched sibling donor.

It also has used multi-potent adult stem cell therapy to treat other tissues of the body rather than just the marrow and blood-stimulating stem cell gene correction in these patients. Fanconi Anemia is just one of several diseases in which the bone marrow itself fails. Others are sickle cell anemia, thalassemia, Diamond-Blackfan anemia, Kostmann’s neutopenia, ostopetrosis and dyskeratosis congenita progeria.

Children’s Cancer Research Fund: a committed partner

The University of Minnesota is a national referral center for diagnosing, monitoring, and treating children with metabolic diseases. Blood and marrow transplant has been successful for many years, but researchers are on the verge of breakthrough therapy and anxious to accelerate their efforts.

Dr. Paul Orchard, Assistant Professor and Medical Director of the Inherited Metabolic Storage Disease program at the university, said, “Transplants have been used in some of these diseases for quite a while… To move the field forward and actually make things better, we need to integrate other methods with transplant. Fundamentally, that’s one of the main things we want to do here starting in the lab and integrating clinically.”

Children’s Cancer Research Fund supports this work to find better options for the littlest patients.

Addressing needs. Providing options.

Metabolic diseases are complex and require multi-disciplinary treatment. At the University of Minnesota, comprehensive care includes not only the underlying genetic problem, but also the medical, psychological and emotional issues that often accompany metabolic diseases. Clinical expertise at the University of Minnesota exists in the necessary subspecialties of cardiology, ENT, pulmonology, endocrinology, anesthesiology and ophthalmology.

This coordinated care, combined with leading research and long-term follow-up, is one reason the university is a national referral center for diagnosing, monitoring and treating children with metabolic diseases.

Future work

Blood and marrow transplant has been successful for many years, but researchers are on the verge of breakthrough therapy and anxious to accelerate their efforts. “The key is to integrate research into clinical practice,” said Tolar. “We want to advance our treatment of these kids.”

New research on enzyme replacement therapies, either alone or in conjunction with blood and marrow transplant, holds promise to improve outcomes and reduce transplant-related complications. The University of Minnesota is the only institution in the United States to study this combination therapy.

In most of these conditions, bone marrow transplantation can often arrest the course of the disease, but it is not without risk. “Ninety percent of my work with these children is fixing the damage I’ve done with chemotherapy and a BMT” said Dr. Tolar.

Physicians want better treatments than the ones currently available. Tolar and his team are pioneering an innovative treatment using the patient’s skin cells to create immature cells known as induced pluripotent stem cells. Through gene targeting, they will then replace defective genes with new ones, resulting in stem cells that can differentiate into blood-forming cells.

The end result is a renewable source of patient-specific, gene-corrected stem cells, which can differentiate into blood forming cells. This work holds the promise of treatment without a BMT.


These diseases are degenerative

Genetic disease program’s key initiatives:
  • Epidermolysis Bullosa: to continue clinical trial to treat this disease.
  • Metabolic storage disease: to deliver drugs into the brain more effectively
  • Understanding the effects of diet to understand the connection between the diet of a pregnant woman and her child’s risk of developing cancer
  • Working with man’s best friends to take advantage of the similarities between human and canine brain tumors

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