Topical genetic modulation therapy makes inroads

For genetic skin diseases, the future is nearly here.

"It seems like every other day there’s another article published based on using next-generation gene sequencing to find out what’s causing disease, and then using that information to work toward personalized gene and pharmacologic therapy," said Dr. Amy Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University, Chicago. "We’re talking about these things not only in the very near future, but right now."

Viral vectors have made possible enormous advances in the treatment of genetic skin disorders, but they are far from perfect, Dr. Paller said in an interview. Researchers are looking beyond them, hoping to sidestep their problems while capitalizing on the delivery of genetic material to highly targeted areas.

"The problem with viral vectors – and particularly with the ones that are out there now – is that they insert their genetic information randomly into the chromosome. If they insert it into the wrong place, it can cause oncogenesis. We know that leukemia and lymphomas have developed because of this. The next frontier is to develop other techniques" that would avoid the problem altogether, she said at the Hawaii Dermatology Seminar, sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

One of the most exciting areas of research is the topical delivery of genetic therapy, she said. Researchers are wrestling with the problem of effectively delivering molecules to target areas.

"Getting through the epidermal barrier is a major problem for topical genetic modulation therapy. What we are trying to do is conquer this barrier using physical or chemical techniques to decrease its integrity."

A number of methods are under investigation, including microneedles coated with the desired genetic material, which can be injected into very specific sites.

Topically delivering therapeutic nanoparticles is another hot area. Last summer, Dr. Paller’s team obtained some early positive results with spherical nucleic acid nanoparticle conjugates – gold cores surrounded by small interfering RNA. They used a commercially available topical emollient as the vehicle and showed that the nanoparticles penetrated almost 100% of keratinocytes in both mouse and human epidermis. The treatment induced a complete knockdown of epidermal growth factor receptor expression and, in hairless mice, decreased skin thickness by 40%.

One big benefit of this approach is that it requires no compromise of the epidermal barrier, Dr. Paller said. Treatment doesn’t appear to induce any inflammatory cytokines or lead to local or systemic toxicity.

Her lab has moved on from animal models to humans. "We’re looking at real disease now, working on skin cancers and wound healing, psoriasis, and dominant negative keratin gene disorders."

But although the field of gene therapy is rapidly progressing, the process of diagnosis seems mired in the past.

"Diagnosis of genetic disease is still made clinically," Dr. Paller said. While diagnosis can be supplemented by information on family history, extracutaneous exams, and other testing, most children in the U.S. don’t get a complete genetic work-up to pinpoint their unique problem. "In Europe, many children with genetic skin disease undergo genotype analysis, but only a minority of children in the United States does so."

Cost is probably the biggest barrier, "especially without insurance, or if insurance won’t cover the testing. For example, testing six genes for autosomal recessive congenital ichthyosis in a collodion baby can cost more than $12,000."

Some argue that the testing doesn’t provide much practical information. "There are limited genotype-phenotype correlations that predict prognosis," Dr. Paller said. "And unless the information is used for family planning purposes, it has limited value."

Fortunately, genotyping technology is improving even as the cost is coming down. Next-generation sequencing can analyze the entire genome, and even whole-exome sequences – a refinement that could identify about 85% of mutations and allows a detailed look at very small, specific regions. Experts predict that the cost of next-generation sequencing is going to decrease exponentially over the next few years, into the range of $1,000-$5,000.

Leveraging next-generation sequencing could help patients with genetic skin disorders in a number of ways, Dr. Paller said. In addition to finding low-frequency mutations in known genes, the process could identify mutations in newly associated genes and pave the way for the genotype-phenotype correlations that could help diagnosis.

Next-generation sequencing might even make it possible to predict drug response, leading to a truly individualized prescription of genetic treatment, Dr. Paller said.

"These discoveries have translated into new therapy for patients with genetic disorders and will guide innovative treatment in the future. New technology will revolutionize our knowledge of the human genome and disease, facilitating mutation-based gene and pharmacologic therapy."

SDEF and this news organization are owned by the same parent company.

*This story was updated March 1, 2013.

For genetic skin diseases, the future is nearly here.

"It seems like every other day there’s another article published based on using next-generation gene sequencing to find out what’s causing disease, and then using that information to work toward personalized gene and pharmacologic therapy," said Dr. Amy Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University, Chicago. "We’re talking about these things not only in the very near future, but right now."

Viral vectors have made possible enormous advances in the treatment of genetic skin disorders, but they are far from perfect, Dr. Paller said in an interview. Researchers are looking beyond them, hoping to sidestep their problems while capitalizing on the delivery of genetic material to highly targeted areas.

"The problem with viral vectors – and particularly with the ones that are out there now – is that they insert their genetic information randomly into the chromosome. If they insert it into the wrong place, it can cause oncogenesis. We know that leukemia and lymphomas have developed because of this. The next frontier is to develop other techniques" that would avoid the problem altogether, she said at the Hawaii Dermatology Seminar, sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

One of the most exciting areas of research is the topical delivery of genetic therapy, she said. Researchers are wrestling with the problem of effectively delivering molecules to target areas.

"Getting through the epidermal barrier is a major problem for topical genetic modulation therapy. What we are trying to do is conquer this barrier using physical or chemical techniques to decrease its integrity."

A number of methods are under investigation, including microneedles coated with the desired genetic material, which can be injected into very specific sites.

Topically delivering therapeutic nanoparticles is another hot area. Last summer, Dr. Paller’s team obtained some early positive results with spherical nucleic acid nanoparticle conjugates – gold cores surrounded by small interfering RNA. They used a commercially available topical emollient as the vehicle and showed that the nanoparticles penetrated almost 100% of keratinocytes in both mouse and human epidermis. The treatment induced a complete knockdown of epidermal growth factor receptor expression and, in hairless mice, decreased skin thickness by 40%.

One big benefit of this approach is that it requires no compromise of the epidermal barrier, Dr. Paller said. Treatment doesn’t appear to induce any inflammatory cytokines or lead to local or systemic toxicity.

Her lab has moved on from animal models to humans. "We’re looking at real disease now, working on skin cancers and wound healing, psoriasis, and dominant negative keratin gene disorders."

But although the field of gene therapy is rapidly progressing, the process of diagnosis seems mired in the past.

"Diagnosis of genetic disease is still made clinically," Dr. Paller said. While diagnosis can be supplemented by information on family history, extracutaneous exams, and other testing, most children in the U.S. don’t get a complete genetic work-up to pinpoint their unique problem. "In Europe, many children with genetic skin disease undergo genotype analysis, but only a minority of children in the United States does so."

Cost is probably the biggest barrier, "especially without insurance, or if insurance won’t cover the testing. For example, testing six genes for autosomal recessive congenital ichthyosis in a collodion baby can cost more than $12,000."

Some argue that the testing doesn’t provide much practical information. "There are limited genotype-phenotype correlations that predict prognosis," Dr. Paller said. "And unless the information is used for family planning purposes, it has limited value."

Fortunately, genotyping technology is improving even as the cost is coming down. Next-generation sequencing can analyze the entire genome, and even whole-exome sequences – a refinement that could identify about 85% of mutations and allows a detailed look at very small, specific regions. Experts predict that the cost of next-generation sequencing is going to decrease exponentially over the next few years, into the range of $1,000-$5,000.

Leveraging next-generation sequencing could help patients with genetic skin disorders in a number of ways, Dr. Paller said. In addition to finding low-frequency mutations in known genes, the process could identify mutations in newly associated genes and pave the way for the genotype-phenotype correlations that could help diagnosis.

Next-generation sequencing might even make it possible to predict drug response, leading to a truly individualized prescription of genetic treatment, Dr. Paller said.

"These discoveries have translated into new therapy for patients with genetic disorders and will guide innovative treatment in the future. New technology will revolutionize our knowledge of the human genome and disease, facilitating mutation-based gene and pharmacologic therapy."

SDEF and this news organization are owned by the same parent company.

*This story was updated March 1, 2013.

For genetic skin diseases, the future is nearly here.

"It seems like every other day there’s another article published based on using next-generation gene sequencing to find out what’s causing disease, and then using that information to work toward personalized gene and pharmacologic therapy," said Dr. Amy Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University, Chicago. "We’re talking about these things not only in the very near future, but right now."

Viral vectors have made possible enormous advances in the treatment of genetic skin disorders, but they are far from perfect, Dr. Paller said in an interview. Researchers are looking beyond them, hoping to sidestep their problems while capitalizing on the delivery of genetic material to highly targeted areas.

"The problem with viral vectors – and particularly with the ones that are out there now – is that they insert their genetic information randomly into the chromosome. If they insert it into the wrong place, it can cause oncogenesis. We know that leukemia and lymphomas have developed because of this. The next frontier is to develop other techniques" that would avoid the problem altogether, she said at the Hawaii Dermatology Seminar, sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

One of the most exciting areas of research is the topical delivery of genetic therapy, she said. Researchers are wrestling with the problem of effectively delivering molecules to target areas.

"Getting through the epidermal barrier is a major problem for topical genetic modulation therapy. What we are trying to do is conquer this barrier using physical or chemical techniques to decrease its integrity."

A number of methods are under investigation, including microneedles coated with the desired genetic material, which can be injected into very specific sites.

Topically delivering therapeutic nanoparticles is another hot area. Last summer, Dr. Paller’s team obtained some early positive results with spherical nucleic acid nanoparticle conjugates – gold cores surrounded by small interfering RNA. They used a commercially available topical emollient as the vehicle and showed that the nanoparticles penetrated almost 100% of keratinocytes in both mouse and human epidermis. The treatment induced a complete knockdown of epidermal growth factor receptor expression and, in hairless mice, decreased skin thickness by 40%.

One big benefit of this approach is that it requires no compromise of the epidermal barrier, Dr. Paller said. Treatment doesn’t appear to induce any inflammatory cytokines or lead to local or systemic toxicity.

Her lab has moved on from animal models to humans. "We’re looking at real disease now, working on skin cancers and wound healing, psoriasis, and dominant negative keratin gene disorders."

But although the field of gene therapy is rapidly progressing, the process of diagnosis seems mired in the past.

"Diagnosis of genetic disease is still made clinically," Dr. Paller said. While diagnosis can be supplemented by information on family history, extracutaneous exams, and other testing, most children in the U.S. don’t get a complete genetic work-up to pinpoint their unique problem. "In Europe, many children with genetic skin disease undergo genotype analysis, but only a minority of children in the United States does so."

Cost is probably the biggest barrier, "especially without insurance, or if insurance won’t cover the testing. For example, testing six genes for autosomal recessive congenital ichthyosis in a collodion baby can cost more than $12,000."

Some argue that the testing doesn’t provide much practical information. "There are limited genotype-phenotype correlations that predict prognosis," Dr. Paller said. "And unless the information is used for family planning purposes, it has limited value."

Fortunately, genotyping technology is improving even as the cost is coming down. Next-generation sequencing can analyze the entire genome, and even whole-exome sequences – a refinement that could identify about 85% of mutations and allows a detailed look at very small, specific regions. Experts predict that the cost of next-generation sequencing is going to decrease exponentially over the next few years, into the range of $1,000-$5,000.

Leveraging next-generation sequencing could help patients with genetic skin disorders in a number of ways, Dr. Paller said. In addition to finding low-frequency mutations in known genes, the process could identify mutations in newly associated genes and pave the way for the genotype-phenotype correlations that could help diagnosis.

Next-generation sequencing might even make it possible to predict drug response, leading to a truly individualized prescription of genetic treatment, Dr. Paller said.

"These discoveries have translated into new therapy for patients with genetic disorders and will guide innovative treatment in the future. New technology will revolutionize our knowledge of the human genome and disease, facilitating mutation-based gene and pharmacologic therapy."

SDEF and this news organization are owned by the same parent company.

*This story was updated March 1, 2013.