|Year : 2006 | Volume
| Issue : 3 | Page : 211-216
|Gene therapy in dermatology
Institute of Allergic and Immunologic Skin Diseases, Kolkata, India
P. N. Colony, Sapuipara, Bally, Howrah - 711 227
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sarma N. Gene therapy in dermatology. Indian J Dermatol 2006;51:211-6
| Introduction|| |
Introduction of a normal gene into cells or tissues which have defective genes for the treatment of genetic disease is called gene therapy. However gene therapy for the non-genetic diseases has also been attempted.
Non-therapeutic use include prevention or understanding the pathogenesis of a disease. Although delivery of the genes into the cells requires similar techniques, they are by definition not gene therapy.
The basic technique of gene therapy
Introduction of a correct gene replacing a defective one will re-establish the normal functioning of the body. A functional gene can be introduced in the cell by different methods. Most common method that is used currently is to insert the gene into a non-specific location of genome and it replaces a non-functional gene.
However the better approaches are to replace the defective gene with a correct gene through homologous recombination, or use of selective reverse mutation to normalise the defect and synthesize a normal mRNA.
Different techniques of genetic corrections are gene restoration, gene augmentation, gene correction and gene inhibition. In erythropoietin-responsive anaemia, gene augmentation is required.
In case of small point mutations leading to development of a defective gene, gene correction is needed using small DNA/RNA chimeric molecules.
Antisense nucleic acids and ribozymes are two methods of gene inhibition.
In-vivo vs ex-vivo technique of gene therapy
In vivo technique means the genes are delivered directly in the skin of the host by different methods like injection, electroporation, gene gun, topical application to normal and wounded skin surfaces and bioplastic particle insertion etc. In contrast, in ex-vivo technique, the gene is transferred into the cells out side the body into the skin cells taken out. It produces a much higher level of transduction, precisely introduce the gene in correct types of target cells (keratinocytes, or fibroblasts) and there is less chance of immune reaction.
Mice are used in almost all studies of in vivo keratinocyte gene therapy. However recently this has been questioned due to morphological differences between the mice and human skin.
The molecule that carries the therapeutic gene to the target gene or cell is called vector. Vectors are of basically two types, viral and non-viral. Success of a gene therapy depends heavily on proper selection of vector.
By definition, the retrovirus has RNA as the sole genetic material. This is converted by 'reverse transcriptase' to DNA and then it is attached with host DNA by another enzyme called 'integrase'. Retroviruses attach themselves to a arbitrary location in the host's DNA. This can have some serious implication. It can break some important regulatory gene or more seriously can disrupt some growth regulator leding to uncontrolled growth and even development of cancer. To prevent this, specialised techniques have been developped like use of 'zinc finger nucleases' or incorporation of specific sequences such as the 'beta-globin locus control region'.
Unlike retrovirus, genetic mateials of adenovirus, which is a double-stranded DNA, cannot attach themselves with the host DNA and float free in the the nucleus of the host cell. So it is not transmitted to the descendants of the host cell. So repeated treatment is required to treat the newly generated cells.
| Adeno-associated viruses (AAV)|| |
They are non-pathogenic parvovirus having a single stranded DNA. They can infect quiescent cells like neuron. It makes them most suitable to use for treatment of brain disease. They are also very suitable for treatment of muscle and eye disease. However they stimulate strong immune reaction.
Non viral vectors are safer than viral one but have poor transduction capacity with an average rate of only 30%. To improve this 'electroporation' or 'gene gun' techniques have been developed. Elctroporation based newer transfection method has increased the transduction rate to a somewhat higher value of 56%. Further advancement to improve this transient gene expression has developped P-1 based artificial chromosome (PAC construct) and its capacity has been tested to produce stable type VII collagen gene expression in DEB.
Naked DNA is histone-free DNA that gives a new phenotype to the recipient cell during 'transformation' process. Naked DNA plasmid or even naked PCR product has been used in gene therapy. Gene therapy using naked DNA is simple, safe and an efficient method. The plasmid DNA is directly intradermally injected. The gene is incorporated mainly to the keratinocytes and very little to the fibroblast and selectively expressed at upper and middle layer of epidermis., However semiquantitative analysis of the result of transgene expression of IL-6 gene showed that intially it is incorporated into the basal keratinocytes but the expression was lost early to remain in the spinous layer for a prolonged period.
Recently Hengge et al suggested a specific receptor for the plasmid DNA on the surface of keratinocytes. In another intersting development, a small transporter protein called 'high mobility group 1' has been detected in the nucleus of keratinocytes that assists in transport of DNA from cytosol to nucleus.
| Hybrid Methods|| |
Here viral vectors are combined with nonviral vectors, e.g., virosomes.
Hurdles of gene therapy:
l Transient gene expression
l Immune reaction
l Problems with viral vectors
l Multigene disorders
l Chance of inducing a tumor
Reasons of transient gene expression:
1. Poor selection of holoclone keratinocytes.
2. Retroviral vectors produce longer gene expression than non viral vectors or adenovirus.
3. Transient gene expression may be down-regulated due to methylation induced silencing of promoter element by the host.,
4. Episomal expression vector is lost during progeny segregation.
Strategies for sustained gene expression
1. Viral vectors can help prolonged gene expression especially lentiviruses directed to dermal fibroblasts and endothelial cells and AAV directed to the panniculus carnosus. Unfortunately the panniculus carnosus is not present in human beings.
2. Pseudotyped retrovirals when placed invivo under wound eschar produced via dermabrasion can generate persistent gene expression.
| Immune Reaction|| |
Immunology has been in the centre of attention of recent research work. Introduced gene as well as the viral vectors are protein structure (especially the protein envelop). So it faces all the consequence of any foreign proteins inside the body. Both CD4 and CD8 cells participate in the immune response. More importantly, immune reaction elicited by memory cells in subsequent therapies makes the situation worse. Viral vectors have been found to stimulate dendritic cells (DC) through type 1 interferons and phosphatidylinositol 3-kinase pathway.
Ways to prevent immune reaction
1. Generation of tolerogenic DC with the help of IL10 treatment, ligation of CD45RO/RB and NVP347 treatment.,
2. Role of 'Tregs' (transfer of regulatory T cells): Depletion of Tregs can lead to increased tumor growth. Tregs has the potential to be used as treatment option for transplant rejection and autoimmunity and also in preventing immunoreactivity in gene therapy.
3. Blockade of CD28 and CD40 pathway, antibody to CD45RB and other strategies.
| Gene therapy in skin the advantages|| |
Keratinocytes are the target cells of choice in gene therapy for skin diseases and many systemic diseases. The reasons are :
1. Keratinocytes are easily accessible.
2. Rich vascularization in dermis.
3. The genetically modified regions can be easily monitored.
4. Surgical removal of aberrant tissue if required.
5. Skin is a versatile bioreactor: It can synthesize and secrete the proteins into the systemic circulation. It has been found that when transduced with the transgene of growth hormone, transferrin, erythropoietin, apolipoprotein E and factor IX, it delivered the active factors into the circulation.,,,, It has been seen that not only the transgene products are secreted in the circulation, the physiological effects of these transgenes are also observed. Their ability to secret the gene products in the circulation has been further enhanced with recent advancement in approaches like modified progesterone receptor driven transcription. A study has shown that nearly 70 proteins were secreted into the medium by the keratinocytes. Studies have shown that even cytokines like IL4, IL6, IL10, monocyte chemotactic and activating factor (MCAF), GM-CSF, IFN gamma etc., can be synthesized in this way in tranduced keratinocytes followed by systemic secretion. It has been found that a single direct injection of erythropoietin gene with lentiviral vector into human skin xenografts on immune deficient mice produced persistent elevation of hematocrit for nearly 1 year.
Other than keratinocytes, fibroblast, melanocytes, macrophage, endothelial cells all have been used as target cells in skin gene therapy.
Melanocytes are difficult to study because of scarcity of avilable vectors for efficient transduction in the melanocytes. Adenovirus can transduce in the melanocytes but are very short lasting. Lentivirus has been found to have the most efficient transduction capacity (95-100%) and persist for several weeks in 95-100% of the infected melanocytes.
Target sub-population of cells: Role of stem cell
Studies proved that gene therapy targeting stem cells offer longer duration of gene expression than other cells because, with cell divisions, such stem cells are not depleted. Transgene expression has been observed for the entire lifespan of those stem cells (more than 150 cell generations).
Stem cells in keratinocyte population is called holoclone keratinocytes. These are the best target cells for gene therapy. Intermediate meroclones can also be targeted as the T cells in treatment of blood disorders.
| Gene therapy in dermatology|| |
Genetic diseases are the targets for gene therapy, especially the monogenetic diseases. Treatment of recessive patterns is easier as correction of only one defective gene can correct the defect in comparison to the dominant patterns where single gene correction cannot correct the defect, except in happloinsufficiency. Other than genetic diseases, important advancement has been made in the treatment skin cancer, skin wounds and intractable inflammatory skin disease.,,
| Inherited Skin Disorders|| |
Epidermolysis bullosa (EB)
Till date, defect in ten etiological genes have been identified. A good number of EB cases develop aggressive squamous cell carcinoma. So the benefit of gene therapy outweighs the risk associated with it, especially considering the fact of unavailability of any acceptable therapy.
EB simplex (EBS)
Mutation affects the KRT5 and KRT14 keratin genes. Oligonucleotide mediated gene correction techniques have been used. In addition, related techniques like antisense technology and RNA interference have also been used.
1. It is inherited dominantly. So gene therapy is difficult.
2. Mutant allele acts a poison to the cell requiring silencing of that in addition to introduction of a correct gene. Specific slilencing is a potentially promising approach but silencing of the mutant allele without attacking the neighbouring normal one, is extremely difficult. Inspite of these difficulties, success of some studies offers hope in the treatment of EBS.
Junctional EB (JEB)
Traditionally it has been divided into two types - Herlitz (H-JEB) and non-Herlitz (NH-JEB) types. LAMA3, LAMB3 and LAMC2 genes encode three chains of laminin 5- a3, b3 and c2 respectively. LAMB3 gene is the most frequently affected gene by mutations in H-JEB.
Retroviral vector has been the most effetive vector as found in the work by Dellambra et al and Robbins et al using LAMB3 cDNA gene.
Ortiz-Urda et al used a non-viral vector called FC31 integrase, a transporon (sleeping beauty) using 'cut and paste' techniques.
Both BP180-deficient and laminin - 5-deficient junctional EB have been corrected via ex-vivo technique using human skin graft/immune deficient mouse xenograft model.,
Large sizes of the defective genes are major hurdles in the therapy of DEB. Sizes of type VII collagen and plectin cDNA are 9 and 14kb respectively, making them difficult to transport via available vectors. However Sawamura et al recently was able to introduce a 9kb gene via a plasmid DNA.
In-vivo approaches have been made with intradermal injection of:
1. Gene-corrected RDEB fibroblast.
2. Lentiviral vectors carrying the ColVII gene.
3. Recombinant human type collagen.
In an intersting article, Maki Goto et al showed that fibroblast is a better target cell than keratinocyte as the former produced higher amount of collagen VII.
| Xeroderma pigmentosum|| |
This is a genetic disorder transmitted via both dominant and recessive modes. The patients suffer from inefficient nucleotide repair (NER) of ultraviolet ray (UV) induced mutations in DNA. NER is the most efficient DNA repair system, so defect in this culminates in serious mutagenesis and finally skin cancers in most, even before 30 years of age.
Seven genes have been identified from XPA to XPG, defect in which result in NER defect in XP.
Considering the advantage of adenoviruses over retroviruses like capacity to transduce into neurone cells and selective location for transfection, they are used more frequently. Studies by other authors found that lentivirus could be an attractive alternative vector due to its stability and highly efficient transduction into the postmeiotic neurones., Study on viral-mediated expression of XP in fibroblasts has been found to correct the DNA repair deficiency of primary skin fibroblasts isolated from these patients.
However to avoid the risk of insertional mutagenesis, use of plasmid DNA vector should be considered.
| Ichthyosis|| |
Lamellar ichthyosis (LI) is a recessive, X-linked disorder due to a defect in enzyme transglutaminase (Tgase1) that is involved in the formation of the cornified epithelium (CE)
Choate et al have shown that in-vitro retroviral transduction of primary keratinocytes taken from affected LI patients could restore defective involucrin cross-linking and filaggrin and restored the function of the cutaneous barrier in immunodeficient mice.
X-linked ichthyosis is caused by a deficiency in steroid sulphatase (STS). There is accumulation of cholestrol sulphate called 'arylsulphatase C'. Clinically it resuls in abnormal scaling skin.
In 90% of cases, the gene is completely deleted and in the rest, it is partially deleted. Transfection in vitro with the gene encoding STS leads to increased cell maturation and partial correction of the phenotype. The major challenge is early loss of transgene expression which is more common with nonviral naked DNA or plasmid mediated methods than with retroviral vector driven transduction.
Other types of ichthyosis
There is sufficient hope for correction of congenital bullous ichthyosiform erythroderma of the Brocq and Siemens types, caused by mutations in keratins 1, 2e or 10. Antisense probe targeted against a mutated allele to knock out the expression of the dominant negative protein can correct the defect. But practically it is yet to be achieved because of two reasons. A good antisense is hard to find and more importantly the location of the mutation varies widely in families.
Porthyria is a disorder of haematopoitic system. However skin symptoms are marked in most of them. Erythropoietic protoporphyria (EPP) is caused by a ferrochelatase deficiency and is characterized by severe skin photosensitivity and accumulation of protoporphyrin in bone marrow, RBC and some other organs. Gene therapy for this disease has been tried with a self-inactivating lentiviral vector containing human ferrochelatase cDNA driven by the human ankyrin-1/b-globin HS-40 chimeric erythroid promoter/enhancer in mice. Specific ferrochelatase gene was efficiently transferred in bone marrow erythroid lineage that corrected almost all clinical and biological alterations including skin photosensitivity
There are certain differences of a wound from genodermatoses so also in the gene therapy:
1. The epidermal barrier is lacking so gene transfer is easier.
2. Area to be treated is limited.
3. Requirement for gene expression is for only limited period till the ulcer is healed.
So the methods, which classically produce short lasting gene expreesion like nonintegrative viral vectors, can be used.
Gene-gun delivery, direct application of naked DNA, electroporative transfer, intraulcer injection, microvascular transfection or wound bed implantation are other techniques used.
Gene therapy offers valuable treatment options for non-genetic diseases such as severe burns and refractory skin wounds of decubital, vascular or diabetic origin. It aims at enhancing wound-healing rate, inhibiting postulcer complications, e.g., scarring and keloid formation, as well as increasing the tensile strength of newly formed skin.
In-vivo approach has shown that expression of exogenous epidermal growth factor in the skin increases wound healing by 20%.
Collagen-embedded PDGF-B DNA plasmid  or a viral vector carrying the PDGF-B gene  has been introduced in rabbit to improve healing. PDGF-A, KGF, insulin like growth factor (IGF-1) genes have been transduced for increasing the granulation tissue synthesis in other studies. Exogenous expression of IGF enhanced keratin growth in vitro and stimulated proliferation in vivo , without altering epidermal differentiation
Pre-clinical studies have been undertaken in vivo with VEGF, iNOS and EGR 1 (early growth response factor 1) genes for increasing the vascularization to a similar degree. EGF and GH genes were used for repithelialization.
Of particular interest is use of TGF-b and FGF genes in preventing scarring and fibrosis during wound healing. Antisense oligonucleotides have been used to enhance functioning of collagen genes.
Squamous cell carcinoma (SCC)
Successful treatment of SCC in mice by transfection with herpes simplex thymidine kinase (HSVTK) 'suicide' gene followed by treatment with gancyclovir by a adenovirus marked an important progress towards cancer gene therapy.
Quite a few studies have been undertaken for treatment of melanoma with gene therapy, like genetically modified fibroblasts, tumour cells, direct injection of vaccinia and adenoviruses encoding cytokines.
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