Patient-Specific Stem Cells Plus Personalized Gene Therapy for Blindness


Researchers from Columbia University Medical Center (CUMC) have devised protocols to develop personalized gene therapies for patients with an eye known as retinitis pigmentosa (RP), which is a leading cause of vision loss. While RP can begin during infancy, the first symptoms typically emerge during early adulthood. Typically the disease begins with night blindness, and RP eventually progresses to rob the patients of their peripheral vision. In its later stages, RP destroys photoreceptors in the macula, that region of the retina that provides the best vision under lighted conditions. RP is estimated to affect at least 75,000 people in the United States and 1.5 million worldwide.

The approach utilized by this Columbia team utilizes induced pluripotent stem (iPS) cell technology to transform patient’s skin cells into retinal cells, which are then used as a patient-specific model for disease study and preclinical testing.

The leader of this research group, Stephen H. Tsang, MD, PhD, showed that a form of RP caused by mutations to the MFRP gene compromised the structural integrity of the retinal cells. The MFRP gene encodes a protein called the Membrane Frizzled-Related Protein, which plays an important role in eye development. Mutations in the MFRP gene are associated with small eye conditions such as nanophthalmos, posterior microphthalmia, or retinal issues such as retinitis pigmentosa, foveoschisis, or even optic disc drusen. Tsang and his group, however, showed that the effects of these MFRP mutations could be reversed with gene therapy. Thus this new approach could potentially be used to create personalized therapies for other forms of RP, or even other genetic diseases.

“The use of patient-specific cell lines for testing the efficacy of gene therapy to precisely correct a patient’s genetic deficiency provides yet another tool for advancing the field of personalized medicine,” said Dr. Tsang, the Laszlo Z. Bito Associate Professor of Ophthalmology and associate professor of pathology and cell biology. This work was recently published in the online edition of Molecular Therapy, the official journal of the American Society for Gene & Cell Therapy.

Mutations in more than 60 different genes have been linked to RP. Such a genetic disease is known as a heterogeneous trait and genetic diseases like RP or deafness or other such conditions are very difficult to develop models to study. Animal models, though useful, have significant limitations because of interspecies differences. Eye researchers have also used human retinal cells from eye banks to study RP. This eye tissue comes from the eyes of patients who suffered from the disease and donated their eye tissue to research after death. Unfortunately, despite their usefulness, donated eye tissues typically illustrate the end stage of the disease process. Despite their usefulness, they reveal little about how RP develops. Also, there are no human tissue culture models of RP, since it is dangerous to harvest retinal cells from patients. Finally, human embryonic stem cells could be useful in RP research, but they are fraught with ethical, legal, and technical issues.

However, the Tsang group used iPS technology to transform skin cells from RP patients, each of whom harbored a different MFRP mutation, into retinal cells. Thus they created patient-specific models for studying the disease and testing potential therapies. Because they used iPS technology, Tsang found a way around the limitations and concerns and dog embryonic stem cells. Thus researchers can induce the patient’s own skin cells and de-differentiated them to a more basic, embryonic stem cell–like state. Such cells are “pluripotent,” which means that they can be transformed into specialized cells of various types.

When Tsang and others analyzed these patient-specific cells, they discovered that the primary effect of MFRP mutations is to disrupt the regulation of a cytoskeletal protein called actin, the scaffolding that gives the cell its structural integrity. “Normally, the cytoskeleton looks like a series of connected hexagons,” said Dr. Tsang. “If a cell loses this structure, it loses its ability to function.” They also found that MFRP works in tandem with another gene, CTRP5, and that a balance between the two genes is required for normal actin regulation.

In the next phase of the study, the CUMC team used adeno-associated viruses (AAVs) to introduce normal copies of MFRP into the iPS-derived retinal cells. This successfully restored the cells’ function. Tsang and others used gene therapy to “rescue” mice with RP due to MFRP mutations. According to Dr. Tsang, the mice showed long-term improvement in visual function and restoration of photoreceptor numbers.

“This study provides both in vitro and in vivo evidence that vision loss caused by MFRP mutations could potentially be treated through AAV gene therapy,” said coauthor Dieter Egli, PhD, an assistant professor of developmental cell biology (in pediatrics) at CUMC, who is also affiliated with the New York Stem Cell Foundation.

Dr. Tsang thinks this approach could potentially be used to study other forms of RP. “Through genome-sequencing studies, hundreds of novel genetic spelling mistakes have been associated with RP,” he said. “But until now, we’ve had very few ways to find out whether these actually cause the disease. In principle, iPS cells can help us determine whether these genes do, in fact, cause RP, understand their function, and, ultimately, develop personalized treatments.”

Directly Reprogramming Gut Cells into Beta Cells to Treat Diabetes


Type 1 diabetes mellitus results from destruction of insulin-producing beta cells in the pancreas. Diabetics have to give themselves routine shots of insulin. The hope that stem cells offer is the production of cells that can replace the lost beta cells. “We are looking for ways to make new beta cells for these patients to one day replace daily insulin injections,” says Ben Stanger, MD, PhD, assistant professor of Medicine in the Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania.

Some diabetics have had beta cells from cadavers transplanted into their bodies to replace the missing beta cells. Such a procedure shows that replacement therapy is, in principle possible. Therefore, transplanting islet cells to restore normal blood sugar levels in type 1 diabetics could treat and even cure disease. Unfortunately, transplantable islet cells are in short supply, and stem cell-based approaches have a long way to go before they reach the clinic. However, Stanger and his colleagues have tried a different strategy for treating type 1 diabetes. “It’s a powerful idea that if you have the right combination of transcription factors you can make any cell into any other cell. It’s cellular alchemy,” comments Stanger.

New research from Stanger and a postdoctoral fellow in his laboratory, Yi-Ju Chen that was published in Cell Reports, describes the production of new insulin-making cells in the gut of laboratory animals by introducing three new transcription factors. This experiment raises the prospect of using directly reprogrammed adult cells as a source for new beta cells.

In 2008, Stanger and others in Doug Melton’s laboratory used three beta-cell reprogramming factors (Pdx1, MafA, and Ngn3, collectively called PMN) to convert pancreatic acinar cells (the cells in the pancreas that secrete enzymes rather than hormones) into cells that had many of the features of pancreatic beta cells.

Following this report, the Stanger and his team set out to determine if other cells types could be directly reprogrammed into beta cells. “We expressed PMN in a wide spectrum of tissues in one-to-two-month-old mice,” says Stanger. “Three days later the mice died of hypoglycemia.” It was clear that Stanger and his crew were on to something. Further work showed that some of the mouse cells were making way too much extra insulin and that killed the mice.

When the dead mice were autopsied, “we saw transient expression of the three factors in crypt cells of the intestine near the pancreas,” explained Stanger.

They dubbed these beta-like, transformed cells “neoislet” cells. These neoislet cells express insulin and show outward structural features akin to beta cells. These neoislets also respond to glucose and release insulin when exposed to glucose. The cells were also able to improve hyperglycemia in diabetic mice.

Stanger and his co-workers also figured out how to turn on the expression of PMN in only the intestinal crypt cells to prevent the deadly whole-body hypoglycemia side effect that first killed the mice.

In culture, the expression of PMN in human intestinal ‘‘organoids,’ which are miniature intestinal units grown in culture, also converted intestinal epithelial cells into beta-like cells.

“Our results demonstrate that the intestine could be an accessible and abundant source of functional insulin-producing cells,” says Stanger. “Our ultimate goal is to obtain epithelial cells from diabetes patients who have had endoscopies, expand these cells, add PMN to them to make beta-like cells, and then give them back to the patient as an alternate therapy. There is a long way to go for this to be possible, including improving the functional properties of the cells, so that they more closely resemble beta cells, and figuring out alternate ways of converting intestinal cells to beta-like cells without gene therapy.”

This is hopefully a grand start to what might be a cure for type 1 diabetes.

Human Stem Cell Gene Therapy Appears Safe and Effective


Two recent studies in the journal Science have reported the outcome of virally-mediated gene correction in hematopoietic stem cells (HSCs) to treat human patients. These studies may usher in a new era of safe and effective gene therapy. These exciting new clinical findings both come from the laboratory of Luigi Naldini at the San Raffaele Scientific Institute, Milan, Italy. The first experiment examined the treatment of metachromatic leukodystrophy (MLD), which is caused by mutations in the arylsulfatase A (ARSA) gene, and the second, investigated treatments for Wiskott-Aldrich syndrome (WAS), which is caused by mutations in the gene that encodes WASP.

MLD is one of several diseases that affects the lysosome; a structure in cells that acts as the garbage disposal of the cell. So called “lysosomal storage diseases” result from the inability of cells to degrade molecules that come to the lysosome for degradation. Without the ability to degrade these molecules, they build up to toxic levels and produce progressive motor and cognitive impairment and death within a few years of the onset of symptoms.

To treat MLD, workers in Naldini’s laboratory isolated blood-making stem cells from the bone marrow of three pre-symptomatic MLD patients (MLD01, 02 and 03). These stem cells were infected with genetically engineered viruses that encoded the human ARSA gene. After expanding these stem cells in culture, they were re-introduced into the MLD patients after those same patients had their resident bone marrow wiped out. The expression of the ARSA gene in the reconstituted bone marrow was greater than 10 fold the levels measured in healthy controls and there were no signs of blood cancers or other maladies. One month after the transplant, the implanted cells showed very high-level and stable engraftment. Between 45%-80% of cells isolated and grown from bone marrow samples harbored the fixed ARSA gene. AS expected, the levels of the ARSA protein rose to above-normal levels in therapeutically relevant blood cells and above normal levels of ARSA protein were isolated from hematopoietic cells after one month and cerebrospinal fluid (CSF) one to two years after transfusion. This is remarkable when you consider that one year before, no ARSA was seen. This shows that the implanted cells and their progeny properly homed to the right places in the body. The patient evaluations at time points beyond the expected age of disease onset was even more exciting, since these treat patients showed normal, continuous motor and cognitive development compared to their siblings who had MLD, but were untreated. The sibling of the patient designated “MLD01” was wheelchair-bound and unable to support their head and trunk at 39 months, but excitingly, after treatment, patient MLD01 was able to stand, walk and run at 39 months of age and showed signs of continuous motor and cognitive development. Lastly, and perhaps most importantly, there was no evidence of implanted cells becoming cancerous, even though they underwent self-renewal, like all good stem cells. This is the first report of an MLD patient at 39 months displaying such positive clinical features.

The second study treated WAS, which is an inherited disease that affects the immune system and leads to infections, abnormal platelets, scaly skin (eczema), blood tumors, and autoimmunity. In this second study, blood-making stem cells were collected from three patients infected with genetically engineered viruses that expressed the WASP gene. These stem cells were then reinfused intravenously (~11 million cells ) three days after collection. Blood tests and bone marrow biopsies showed evidence of robust engraftment of gene-corrected cells in bone marrow and peripheral blood up to 30 months later. WASP expression increased with time in most blood cells. Although serious adverse infectious events occurred in two patients, overall clinical improvement resulted in reduced disease severities in all patients. None of the three patients demonstrated signs of blood cancers and the platelet counts rose, but, unfortunately, not to normal levels. Again, no evidence for adverse effects were observed.

Simply put, these authors have presented a strategy for ex vivo gene correction in HSCs for inherited disorders which works and appears safe in comparison to previous strategies. Long-term analyses will undoubtedly need to be intensely scrutinized, but this research surely represents a huge step forward in the safe treatment of these and similar genetic disorders.

Stem Cell-Based Gene Therapy Restores Normal Skin Function


Michele De Luca from the University of Modena, Italy and his collaborator Reggio Emilia have used a stem cell-based gene therapy to treat an inherited skin disorder.

Epidermolysis bullosa is a painful skin disorder that causes the skin to be very fragile and blister easily. These blisters can lead to life-threatening infections. Unfortunately, no cure exists for this condition and most treatments try to alleviate the symptoms and infections.

Stem cell-based therapy seems to be one of the best ways to treat this disease, there are no clinical studies that have examined the long-term outcomes of such a treatment.

However, De Luca and his colleagues have examined a particular patients with epidermolysis bullosa who was treated with a stem cell-based gene therapy nearly seven years ago as part of a clinical trial.

The treatment of this patient has established that transplantation of a small quantity of stem cells into the skin on this patient’s legs restored normal skin function without causing any adverse side effects.

“These findings pave the way for the future safe use of epidermal stem cells for combined cell and gene therapy of epidermolysis bullosa and other genetic skin diseases,” said Michele De Luca.

De Luca and his research team found that their treatment of their patient, named Claudio, caused the skin covering his upper legs to looker normal and show no signs of blisters. To treat Claudio, De Luca and his colleague extracted skin cells from Claudio’s palm, used genetic engineering techniques to correct the genetic defect in the cells, and then transplanted these cells back into the skin of his upper legs. This was part of a clinical trial conducted at the University of Modena.

Claudio’s legs also showed no signs of tumors and the small number of transplanted cells sufficiently repaired Claudio’s skin long-term. Keep in mind that Claudio’s skin cells had undergone approximately 80 cycles of cell division and still had many of the features of palm skin cells, they show proper elasticity and strength and did not blister.

“This finding suggests that adult stem cell primarily regenerate the tissue in which they normally reside, with little plasticity to regenerate other tissues,” De Luca said. “This calls into question the supposed plasticity of adult stem cells and highlights the need to carefully chose the right type of stem cell for therapeutic tissue regeneration.”

I think De Luca slightly overstates his case here. Certainly choosing the right stem cells is crucial for successful stem cell treatments, but to take stem cells from skin, which are dedicated to making skin and expect them to form other tissues is unreasonable. However, several experiments have shown that stem cells from hair follicles and form neural tissues and several other cell types as well (see Jaks V, Kasper M, Toftgård R. The hair follicle-a stem cell zoo. Exp Cell Res. 2010 May 1;316(8):1422-8).

Adult stem cells have limited plasticity to be sure, but their plasticity is far greater than originally thought and a wealth of experiments have established that.

Despite these quibbles, this is a remarkable experiment that illustrates the feasibility and safety of such a treatment.  A larger problem is that large quantities of cells will be required to treat a person.  It is doubtful that small skin biopsies around the body can provide enough cells to treat the whole person.  Therefore, this might a case for induced pluripotent skin cells, which seriously complicates this treatment strategy.

Stem-Cell Gene Therapy for Sickle Cell Disease


Donald Kohn, a professor of pediatrics and microbiology, immunology and molecular genetics in the UCLA College of Letters and Science, and his colleagues, have successfully established the means to cure sickle-cell disease. This strategy uses hematopoietic (blood-producing) stem cells from the bone marrow of patients with sickle-cell disease in order to treat the disease itself.

This approach provides a revolutionary alternative to current treatments, since it creates self-renewing, normal blood cells by inserting a gene that abrogates the sickling properties into hematopoietic stem cells. With this technique, there is no need to identify a matched donor, and therefore, patients avoid the risk of their bodies rejecting donor cells.

During the clinical trial, the anti-sickling hematopoietic stem cells will be transplanted back into patients’ bone marrow to increase the population of “corrected” cells that make red blood cells that don’t sickle. Kohn will hopefully begin enrolling patients in the trial within three months. The first subject will be enrolled and observed for safety for six months. The second subject will then be enrolled and observed for safety for three months. If evaluations show that no problems have arisen, the study will continue with two more subjects and another evaluation, until a total of six subjects have been enrolled.

Sickle cell disease, which affects more than 90,000 individuals in the U.S., is seen primarily in people of sub-Saharan African descent. It is caused by an inherited mutation in the beta-globin gene that transforms normal-shaped red blood cells, which are round and pliable, into rigid, sickle-shaped cells. Normal red blood cells are able to pass easily through the tiniest blood vessels (capillaries) and carry oxygen to organs like the lungs, liver and kidneys. However, sickled cells get stuck in the capillaries, depriving the organs of oxygen, which can lead to organ dysfunction and failure.

Current treatments include transplanting patients with hematopoietic stem cells from a donor. This is a potential cure for the disease, but due to the serious risks of rejection, only a small number of patients have undergone this procedure, and it is usually restricted to children with severe symptoms.

“Patients with sickle-cell disease have had few therapeutic options,” Kohn said. “With this award, we will initiate a clinical trial that we hope will become a treatment for patients with this devastating disease.”

Finding for this work comes from new grants to researchers at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, which total nearly $21 million.  These grants were announced Dec. 12 at a meeting of the California Institute of Regenerative Medicine (CIRM) Citizen’s Oversight Committee.  They are apart of the state agency’s Disease Team Therapy Development III initiative.

Gene Therapy Makes Huge Advance in Cancer Fight


Gene therapy has been used to transform patients’ blood cells into soldiers that seek and destroy cancer. A small group of leukemia patients were given a one-time, experimental therapy several years ago and today, some remain cancer-free today. As a follow-up, at least six research groups have treated more than 120 patients with many types of blood and bone marrow cancers, with stunning results.

“It’s really exciting,” says Janis Abkowitz, blood diseases chief at the Univ. of Washington in Seattle and president of the American Society of Hematology. “You can take a cell that belongs to a patient and engineer it to be an attack cell.”

In one study, all five adults and 19 of 22 children with acute lymphocytic leukemia (ALL) showed complete remission of their cancer (i.e. no cancer could be found after treatment), although a few patients have relapsed since then.

These were gravely ill patients who were out of options. Some of them had tried multiple bone marrow transplants and up to 10 types of chemotherapy or other treatments. In the case of eight-year-old Emily Whitehead of Philipsburg, Pa., her cancer was so advanced that her doctors said Emily’s major organs would fail within days. Ms. Whitehead was the first child given the gene therapy and nearly two years later, shows no sign of cancer.

Physicians think that this has the potential to become the first gene therapy approved in the U.S. and the first for cancer worldwide. Only one gene therapy is approved in Europe, for a rare metabolic disease.

This gene therapy involves filtering patients’ blood to remove millions of T-cells, a type of white blood cell. These T-cells are then genetically engineered in the laboratory with a gene that targets cancer. These cells were subsequently returned to the patient in infusions, given over three days.

“What we are giving essentially is a living drug” – permanently altered cells that multiply in the body into an army to fight the cancer, says David Porter, a Univ. of Pennsylvania scientist who led one study.

Several drug and biotech companies are working hard to develop these therapies. The University of Pennsylvania has patented its method and licensed it to the Switzerland-based company Novartis AG. Novartis AG is building a research center on the Penn campus in Philadelphia and plans a clinical trial next year that could lead to federal approval of the treatment as soon as 2016. Hervé Hoppenot, president of Novartis Oncology, the division leading the work, said that “there is a sense of making history… a sense of doing something very unique.” Lee Greenberger, chief scientific officer of the Leukemia and Lymphoma Society, agrees: “From our vantage point, this looks like a major advance. We are seeing powerful responses… and time will tell how enduring these remissions turn out to be.”

This group has given $15 million to various researchers who are testing this strategy. Since there are nearly 49,000 new cases of leukemia, 70,000 cases of non-Hodgkin lymphoma and 22,000 cases of myeloma expected to be diagnosed in the U.S. in 2013, there are no shortage of potential subjects.

Many patients are successfully treated with chemotherapy or bone marrow or stem cell transplants, but transplants are risky and donors can’t always be found. Thus, gene therapy has been used as a fallback strategy for patients who were in danger of dying once all the other treatments failed.

The gene therapy must be made individually for each patient, since laboratory costs now are about $25,000, without a profit margin. That’s still less than many drugs to treat these diseases and far less than a transplant. The treatment can cause severe flu-like symptoms and other side effects, but these have been reversible and temporary, according to the physicians who administer the gene therapy treatment and observe the patients afterwards.

Penn doctors have treated 59 patients so far, which is the most of any center so far. Of the first 14 patients with B-cell chronic lymphocytic leukemia (CLL), four showed complete remissions, four showed partial remission, and the remaining patients did not respond to the treatment. However, some of the patients who showed partial remission continued to see their cancer shrink a year after treatment. “That’s very unique to this kind of therapy” and gives hope the treatment may still purge the cancer, says Porter.

Another 18 CLL patients were treated and half have responded so far. University of Pennsylvania doctors also treated 27 ALL patients. All five adults and 19 of the 22 children had complete remissions, which is an “extraordinarily high” success rate, according to Stephan Grupp at the Children’s Hospital of Philadelphia (CHOP). Six patients have, since then, suffered relapse of their cancer. The attending physicians are considering administering a second gene therapy treatment.

At the National Cancer Institute, James Kochenderfer and others have treated 11 patients with lymphoma and four with CLL, starting roughly two years ago. Six showed complete remission, six patients had partial remission, and one has stable disease but it is too soon to tell for the rest.

Ten other patients were given gene therapy to try to kill the leukemia or lymphoma cells that remained after bone marrow transplants. These patients received infusions of gene-treated blood cells from their transplant donors instead of using their own blood cells. One had a complete remission and three others had significant reduction of their disease.

“They’ve had every treatment known to man. To get any responses is really encouraging,” Kochenderfer says. The cancer institute is working with a Los Angeles biotech firm, Kite Pharma Inc., on its gene therapy approach.

Patients are encouraged that relatively few have relapsed.

“We’re still nervous every day because they can’t tell us what’s going to happen tomorrow,” says Tom Whitehead, eight-year-old Emily’s father.

Doug Olson, 67, a scientist for a medical device maker, shows no sign of cancer since his gene therapy in September 2010 for CLL he has had since 1996. “Within one month he was in complete remission. That was just completely unexpected,” says Porter, his doctor at Penn. Olson ran his first half-marathon in January and no longer worries about how long his remission will last. “I decided I’m cured. I’m not going to let that hang over my head anymore,” he says.

Stem Cell Treatments for Hurler’s Syndrome


Mucopolysaccharidoses are a group of inherited diseases that result from loss-of-function mutations in those genes that encode enzymes that degrade long-chain sugar molecules. One of these mucopolysaccharidoses, Hurler syndrome, is a consequence of the inability to make a functional version of an enzyme called iduronidase. Without functional iduronidase, cells cannot degrade molecules called glycosaminoglycans (formerly called mucopolysaccharides), which are found in mucus and in fluid around the joints. The concentrations of these glycosaminoglycans increase and damage organs, including the heart. Symptoms can range from mild to severe.

From Kowalewski B et al. PNAS 2012;109:10310-10315. Heparan sulfate catabolism involving GlcNS3S structures. The scheme illustrates all nine different enzymatic activities required for the sequential catabolism of a NRE tetrasaccharide containing GlcNS3S. To expose the 3-O-sulfated residue at the terminus, the preceding uronic acid (iduronate 2-O-sulfate in this example) is modified sequentially by iduronate 2-sulfatase and iduronidase. Under normal conditions, the 3-O-sulfate then is removed from GlcNS3S by ARSG, thus generating the substrate for sulfamidase, which removes the N-sulfate group. Subsequently, another six different enzymes (plus again sulfamidase) have to act, which ultimately leads to a complete degradation of the chain. The loss of ARSG activity (MPS IIIE) leads to the accumulation of 3-O-sulfated ARSG substrate that cannot be acted upon by downstream catabolic enzymes. It should be noted that the 2-O-sulfation shown at the glucuronic acid (third residue) is relatively rare, which agrees with the finding that no pentasulfated trisaccharides were found as NRE structures (Fig. 3A). Scheme modified from Neufeld and Muenzer (6) according to findings from this work and from Lawrence et al.
From Kowalewski B et al. PNAS 2012;109:10310-10315.
Heparan sulfate catabolism involving GlcNS3S structures. The scheme illustrates all nine different enzymatic activities required for the sequential catabolism of a NRE tetrasaccharide containing GlcNS3S. To expose the 3-O-sulfated residue at the terminus, the preceding uronic acid (iduronate 2-O-sulfate in this example) is modified sequentially by iduronate 2-sulfatase and iduronidase. Under normal conditions, the 3-O-sulfate then is removed from GlcNS3S by ARSG, thus generating the substrate for sulfamidase, which removes the N-sulfate group. Subsequently, another six different enzymes (plus again sulfamidase) have to act, which ultimately leads to a complete degradation of the chain. The loss of ARSG activity (MPS IIIE) leads to the accumulation of 3-O-sulfated ARSG substrate that cannot be acted upon by downstream catabolic enzymes. It should be noted that the 2-O-sulfation shown at the glucuronic acid (third residue) is relatively rare, which agrees with the finding that no pentasulfated trisaccharides were found as NRE structures (Fig. 3A). Scheme modified from Neufeld and Muenzer according to findings from this work and from Lawrence et al.

Hurler syndrome is inherited, and both parents must pass the faulty gene to inherit Hurler syndrome.

The symptoms of Hurler syndrome usually appear between ages 3 and 8. Infants with severe Hurler syndrome appear normal at birth. Facial symptoms may become more noticeable during the first 2 years of life. The most common symptoms include abnormal bones in the spine, claw hand, cloudy corneas, deafness, halted growth, heart valve problems, joint disease (including stiffness),
Intellectual disability that gets worse over time, and thick, coarse facial features with a low nasal bridge.

Hurler’s syndrome appears in about 1 in 100,000 live births, and those afflicted with it normally die in their teens.

Treatments for Hurler Syndrome include “enzyme replacement,” which is very expensive. Enzyme replacement therapy utilizes genetic engineering to make large quantities of iduronidase, which is then administered to Hurler Syndrome patients. A second treatment is bone marrow transplantation, but this requires finding a good tissue match.

Sharon Byers from the University of Adelaide, Australia and her colleagues are genetically modifying adult stem cells (mesenchymal stem cells, specifically) to make large quantities of iduronidase. These modified stem cells are then infused into Hurler Syndrome patients. To date, these experimental treatments seem to be providing Hurler Syndrome patients some relief, but it is still early in the trial.

Matilda Jackson, a PhD candidate in Byers lab, described their trial in this manner: “We have turned adult stem cells into little ‘enzyme factories” by coupling them with a virus that makes them pump out high levels of the enzyme.” Matilda Jackson is a member of the School of Molecular and Biochemical Sciences and Adelaide University.

Dr. Jackson continued, “Those stem cells can then be injected into the blood where they move around the body and become liver or bone or brain or other cells and start producing the missing enzyme. They automatically migrate to areas of damage in the affected individual. So far in our laboratory studies we’ve measured improvements in brain function but we’ve yet to complete the analysis to determine if there are improvements in other organs.”

Sharon Byers, an affiliate senior lecturer in the School of Molecular and Biomedical Sciences, explained, “There are two current treatments for Hurler’s Syndrome: costly enzyme replacement therapy or bone marrow transplants which require a perfectly matched donor. And while they bring some improvements,, neither of these treatments prevents damage to the brain and bones because not enough enzyme reaches either of these tissues.”

Dr. Byers continued: “These stem cells, modified so that produce large quantities of the enzyme that people with Hurler’s Syndrome lack, offer great hope for a potential new therapy. If we can help reverse the disease symptoms, we could see these children able to perform normal tasks, giving them a better quality of life and increasing their life span.”