Epidermolysis Bullosa Wounds Heal Quickly After Fibroblast Injections

PORTLAND, Ore. - Wounds from recessive dystrophic epidermolysis bullosa healed more rapidly following injection of their margins with donor allogeneic fibroblasts, according to early study results summarized by Dr. John A. McGrath.

In some cases, wounds caused by recessive dystrophic epidermolysis bullosa (RDEB) healed almost completely within 2 weeks, said Dr. McGrath, professor of molecular dermatology at King’s College London, who is studying the technique.

The procedure is in its earliest stages of clinical investigation, tried so far in just a handful of patients.

And it is not a cure; the healing effect may taper off after several months; reformed wounds would likely need additional injections.

Even so, initial results suggest fibroblast injections could be an “effective approach to therapy for RDEB,” said Dr. Dedee Murrell, professor and chair of the dermatology department at St. George Hospital and the University of New South Wales in Sydney. She is also studying the technique.

Patients with RDEB, which results from a genetic mutation, produce low or no amounts of type VII collagen at the dermal-epidermal junction (DEJ). As a result of the weak or absent fibrils in RDEB,

the slightest skin trauma causes the epidermal layer to blister off, resulting in recurrent wounds, pain, infection, scarring, deformity, digit loss, and failure to thrive. The condition also predisposes patients to squamous cell carcinoma.

Supportive care is the only treatment option at present; the new technique offers the hope of a truly effective intervention.

Though the injected fibroblasts disappear within 2 weeks, they appear to encourage native keratinocytes – and perhaps resident fibroblasts – to increase production of the patient’s own mutant, but partially functional, collagen VII, increasing anchoring fibrils at the junction and leading to better skin adhesion and wound repair.

Those who have a higher baseline expression collagen VII appear to benefit most from the intervention, Dr. McGrath said in an interview following the meeting.

So far, “we have injected [fibroblasts into] wounds in 12 people with RDEB and have observed more rapid skin closure in most subjects. We can show a single injection of fibroblasts increases the patient’s type VII collagen gene expression for 3-6 months, and [collagen VII] expression for 9-12 months,” he said.

Dr. McGrath’s team uses foreskin fibroblast preparations made by Intercytex Ltd. There have been no serious side-effects; antibodies to the donor fibroblasts have not been detected. Patients were 18-35 years old.

They will soon start a phase II RDEB wound-healing trial. “Thereafter, we hope to launch multicenter phase III clinical trials in Europe,” he said.

Dr. McGrath also believes his team has identified a growth factor that triggers collagen VII production at the DEJ and has filed a patent on it through his institution.

The hope is that “we don’t actually need the cells,” Dr. McGrath said.

In Australia, Dr. Murrell’s team has injected allogeneic fibroblasts into the wounds of 5 RDEB patients aged 20-25 years, she said in an interview.

Compared with untreated wounds, those injected rapidly improved; ulcer sizes were at least halved 2 weeks after injection, and continued to heal – or at least did not worsen – after 6 months.

In a surprising twist, Dr. Murrell’s group found that wounds healed equally as well when injected with the fibroblast transport solution, without the cells. Her team used the inert mineral solution Plasma-Lyte with 2% albumen as the transport medium.

“We do not know if it was the needling itself or the placebo solution, or both, that had this beneficial effect,” she said, adding that needling is known to increase skin collagen remodeling. Her team is studying the finding.

Dr. McGrath’s group also found that injecting saline, without cells, increases collagen VII in RDEB skin, probably because of minor inflammation, he said. The investigators also found that the degree and duration of response was considerably less than following fibroblast injection.

But because of Dr. Murrell’s findings, “our future clinical trials will include use of the transport medium – minus the cells – as a control,” he said.

Dr. McGrath noted that other forms of cell therapy also are being studied for RDEB, including intradermal injections of allogeneic, unmatched bone marrow cells and, most recently, whole bone marrow transplantation from matched, related donors (Cytotherapy 2010;12:429-31; N. Engl. J. Med. 2010;363:629-39).

“We should also remember that cell therapy is just one approach; a combination of gene, protein, and drug [therapies] may well be necessary for optimal patient management in the future,” he said.

PORTLAND, Ore. - Wounds from recessive dystrophic epidermolysis bullosa healed more rapidly following injection of their margins with donor allogeneic fibroblasts, according to early study results summarized by Dr. John A. McGrath.

In some cases, wounds caused by recessive dystrophic epidermolysis bullosa (RDEB) healed almost completely within 2 weeks, said Dr. McGrath, professor of molecular dermatology at King’s College London, who is studying the technique.

The procedure is in its earliest stages of clinical investigation, tried so far in just a handful of patients.

And it is not a cure; the healing effect may taper off after several months; reformed wounds would likely need additional injections.

Even so, initial results suggest fibroblast injections could be an “effective approach to therapy for RDEB,” said Dr. Dedee Murrell, professor and chair of the dermatology department at St. George Hospital and the University of New South Wales in Sydney. She is also studying the technique.

Patients with RDEB, which results from a genetic mutation, produce low or no amounts of type VII collagen at the dermal-epidermal junction (DEJ). As a result of the weak or absent fibrils in RDEB,

the slightest skin trauma causes the epidermal layer to blister off, resulting in recurrent wounds, pain, infection, scarring, deformity, digit loss, and failure to thrive. The condition also predisposes patients to squamous cell carcinoma.

Supportive care is the only treatment option at present; the new technique offers the hope of a truly effective intervention.

Though the injected fibroblasts disappear within 2 weeks, they appear to encourage native keratinocytes – and perhaps resident fibroblasts – to increase production of the patient’s own mutant, but partially functional, collagen VII, increasing anchoring fibrils at the junction and leading to better skin adhesion and wound repair.

Those who have a higher baseline expression collagen VII appear to benefit most from the intervention, Dr. McGrath said in an interview following the meeting.

So far, “we have injected [fibroblasts into] wounds in 12 people with RDEB and have observed more rapid skin closure in most subjects. We can show a single injection of fibroblasts increases the patient’s type VII collagen gene expression for 3-6 months, and [collagen VII] expression for 9-12 months,” he said.

Dr. McGrath’s team uses foreskin fibroblast preparations made by Intercytex Ltd. There have been no serious side-effects; antibodies to the donor fibroblasts have not been detected. Patients were 18-35 years old.

They will soon start a phase II RDEB wound-healing trial. “Thereafter, we hope to launch multicenter phase III clinical trials in Europe,” he said.

Dr. McGrath also believes his team has identified a growth factor that triggers collagen VII production at the DEJ and has filed a patent on it through his institution.

The hope is that “we don’t actually need the cells,” Dr. McGrath said.

In Australia, Dr. Murrell’s team has injected allogeneic fibroblasts into the wounds of 5 RDEB patients aged 20-25 years, she said in an interview.

Compared with untreated wounds, those injected rapidly improved; ulcer sizes were at least halved 2 weeks after injection, and continued to heal – or at least did not worsen – after 6 months.

In a surprising twist, Dr. Murrell’s group found that wounds healed equally as well when injected with the fibroblast transport solution, without the cells. Her team used the inert mineral solution Plasma-Lyte with 2% albumen as the transport medium.

“We do not know if it was the needling itself or the placebo solution, or both, that had this beneficial effect,” she said, adding that needling is known to increase skin collagen remodeling. Her team is studying the finding.

Dr. McGrath’s group also found that injecting saline, without cells, increases collagen VII in RDEB skin, probably because of minor inflammation, he said. The investigators also found that the degree and duration of response was considerably less than following fibroblast injection.

But because of Dr. Murrell’s findings, “our future clinical trials will include use of the transport medium – minus the cells – as a control,” he said.

Dr. McGrath noted that other forms of cell therapy also are being studied for RDEB, including intradermal injections of allogeneic, unmatched bone marrow cells and, most recently, whole bone marrow transplantation from matched, related donors (Cytotherapy 2010;12:429-31; N. Engl. J. Med. 2010;363:629-39).

“We should also remember that cell therapy is just one approach; a combination of gene, protein, and drug [therapies] may well be necessary for optimal patient management in the future,” he said.

PORTLAND, Ore. - Wounds from recessive dystrophic epidermolysis bullosa healed more rapidly following injection of their margins with donor allogeneic fibroblasts, according to early study results summarized by Dr. John A. McGrath.

In some cases, wounds caused by recessive dystrophic epidermolysis bullosa (RDEB) healed almost completely within 2 weeks, said Dr. McGrath, professor of molecular dermatology at King’s College London, who is studying the technique.

The procedure is in its earliest stages of clinical investigation, tried so far in just a handful of patients.

And it is not a cure; the healing effect may taper off after several months; reformed wounds would likely need additional injections.

Even so, initial results suggest fibroblast injections could be an “effective approach to therapy for RDEB,” said Dr. Dedee Murrell, professor and chair of the dermatology department at St. George Hospital and the University of New South Wales in Sydney. She is also studying the technique.

Patients with RDEB, which results from a genetic mutation, produce low or no amounts of type VII collagen at the dermal-epidermal junction (DEJ). As a result of the weak or absent fibrils in RDEB,

the slightest skin trauma causes the epidermal layer to blister off, resulting in recurrent wounds, pain, infection, scarring, deformity, digit loss, and failure to thrive. The condition also predisposes patients to squamous cell carcinoma.

Supportive care is the only treatment option at present; the new technique offers the hope of a truly effective intervention.

Though the injected fibroblasts disappear within 2 weeks, they appear to encourage native keratinocytes – and perhaps resident fibroblasts – to increase production of the patient’s own mutant, but partially functional, collagen VII, increasing anchoring fibrils at the junction and leading to better skin adhesion and wound repair.

Those who have a higher baseline expression collagen VII appear to benefit most from the intervention, Dr. McGrath said in an interview following the meeting.

So far, “we have injected [fibroblasts into] wounds in 12 people with RDEB and have observed more rapid skin closure in most subjects. We can show a single injection of fibroblasts increases the patient’s type VII collagen gene expression for 3-6 months, and [collagen VII] expression for 9-12 months,” he said.

Dr. McGrath’s team uses foreskin fibroblast preparations made by Intercytex Ltd. There have been no serious side-effects; antibodies to the donor fibroblasts have not been detected. Patients were 18-35 years old.

They will soon start a phase II RDEB wound-healing trial. “Thereafter, we hope to launch multicenter phase III clinical trials in Europe,” he said.

Dr. McGrath also believes his team has identified a growth factor that triggers collagen VII production at the DEJ and has filed a patent on it through his institution.

The hope is that “we don’t actually need the cells,” Dr. McGrath said.

In Australia, Dr. Murrell’s team has injected allogeneic fibroblasts into the wounds of 5 RDEB patients aged 20-25 years, she said in an interview.

Compared with untreated wounds, those injected rapidly improved; ulcer sizes were at least halved 2 weeks after injection, and continued to heal – or at least did not worsen – after 6 months.

In a surprising twist, Dr. Murrell’s group found that wounds healed equally as well when injected with the fibroblast transport solution, without the cells. Her team used the inert mineral solution Plasma-Lyte with 2% albumen as the transport medium.

“We do not know if it was the needling itself or the placebo solution, or both, that had this beneficial effect,” she said, adding that needling is known to increase skin collagen remodeling. Her team is studying the finding.

Dr. McGrath’s group also found that injecting saline, without cells, increases collagen VII in RDEB skin, probably because of minor inflammation, he said. The investigators also found that the degree and duration of response was considerably less than following fibroblast injection.

But because of Dr. Murrell’s findings, “our future clinical trials will include use of the transport medium – minus the cells – as a control,” he said.

Dr. McGrath noted that other forms of cell therapy also are being studied for RDEB, including intradermal injections of allogeneic, unmatched bone marrow cells and, most recently, whole bone marrow transplantation from matched, related donors (Cytotherapy 2010;12:429-31; N. Engl. J. Med. 2010;363:629-39).

“We should also remember that cell therapy is just one approach; a combination of gene, protein, and drug [therapies] may well be necessary for optimal patient management in the future,” he said.