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Current State of Human Gene Therapy: Approved Products and Vectors
In the realm of gene therapy, a pivotal moment arrived with Paul Berg’s groundbreaking identification of the first recombinant DNA in 1972. This achievement set the stage for future breakthroughs. Conditions once considered undefeatable, like melanoma, pancreatic cancer, and a host of other ailments, are now being addressed at their root cause—the genetic level. Presently, the gene therapy landscape stands adorned with 22 approved in vivo and ex vivo products, including IMLYGIC, LUXTURNA, Zolgensma, Spinraza, Patisiran, and many more. In this comprehensive exploration, we delve into a rich assortment of 16 drugs, from siRNA, miRNA, and CRISPR/Cas9 to DNA aptamers and TRAIL/APO2L, as well as 46 carriers, from AAV, AdV, LNPs, and exosomes to naked mRNA, sonoporation, and magnetofection. The article also discusses the advantages and disadvantages of each product and vector type, as well as the current challenges faced in the practical use of gene therapy and its future potential.
Journal Article
Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells
Fixing the genes in iPS cells
Before human induced pluripotent stem (iPS) cells can be used to treat genetically inherited human disease, it will be necessary to develop methods of correcting disease-causing mutations that are compatible with clinical applications, combining efficiency with efficacy and leaving no residual sequences in the targeted genome. Yusa
et al
. present a proof-of-principle experiment demonstrating the complete genetic correction of a disease-causing mutation in patient-specific iPS cells. They use zinc finger nucleases and piggyBac technology to correction a point mutation in the α
1
-antitrypsin gene, which is responsible for α
1
-antitrypsin deficiency (A1ATD). The corrected iPS cells could efficiently differentiate to form hepatocyte-like cells and engraft into an animal model for liver injury without tumour formation.
Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders
1
,
2
,
3
,
4
. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications
3
,
5
. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome
6
. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs)
7
and
piggyBac
8
,
9
technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α
1
-antitrypsin (
A1AT
, also known as
SERPINA1
) gene that is responsible for α
1
-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells
in vitro
and
in vivo
. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.
Journal Article
Advanced textbook on gene transfer, gene therapy and genetic pharmacology : principles, delivery and pharmacological and biomedical applications of nucleotide-based therapies
This advanced textbook provides a clear and comprehensive description of the field of gene delivery, gene therapy, and genetic pharmacology, with descriptions of the main gene transfer vectors and a set of selected therapeutic applications, along with safety considerations.
Book
Progress and prospects: immune responses to viral vectors
Viral vectors are potent gene delivery platforms used for the treatment of genetic and acquired diseases. However, just as viruses have evolved to infect cells efficiently, the immune system has evolved to fight off what it perceives as invading pathogens. Therefore, innate immunity and antigen-specific adaptive immune responses against vector-derived antigens reduce the efficacy and stability of
in vivo
gene transfer. In addition, a number of vectors are derived from parent viruses that humans encounter through natural infection, resulting in preexisting antibodies and possibly in memory responses against vector antigens. Similarly, antibody and T-cell responses may be directed against therapeutic gene products that often differ from the endogenous nonfunctional or absent protein that is being replaced. As details and mechanisms of such immune reactions are uncovered, novel strategies are being developed, and vectors are being specifically engineered to avoid, suppress or manipulate the response, ideally resulting in sustained expression and immune tolerance to the transgene product. This review provides a summary of our current knowledge of the interactions between the immune system adeno-associated virus, adenoviral and lentiviral vectors, and their transgene products.
Journal Article
Embryonic stem cell trials for macular degeneration: a preliminary report
It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients.
We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration—the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov, numbers NCT01345006 and NCT01344993.
Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).
The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue.
Advanced Cell Technology.
Journal Article
GMOs
An overview of genetic modification and how this biotechnology affects food, humans, animals, and medicine. Includes a discussion of the ethical concerns of genetic biotechnology.
Book
Limbal Stem-Cell Therapy and Long-Term Corneal Regeneration
Corneal damage may become permanent if the supply of limbal stem cells is compromised. In this long-term follow-up study of 113 eyes treated with autologous transplantation of limbal stem-cell cultures, a transparent, renewing corneal epithelium was restored in 77% of eyes and remained stable over time.
Corneal damage may become permanent if the supply of limbal stem cells is compromised. In this long-term follow-up study of 113 eyes treated with autologous transplantation of limbal stem-cell cultures, a transparent, renewing corneal epithelium was restored in 77% of eyes and remained stable over time.
A clear cornea is essential to visual acuity and depends on stromal avascularity and epithelial integrity.
1
Corneal renewal and repair are mediated by stem cells of the limbus, the narrow zone between the cornea and the bulbar conjunctiva.
2
Ocular burns may destroy the limbus, causing limbal stem-cell deficiency. In such cases, the cornea acquires an epithelium through the invasion of bulbar conjunctival cells. This process leads to neovascularization, chronic inflammation, and stromal scarring, with corneal opacity and loss of vision.
3
Allogeneic corneal transplantation (keratoplasty) restores transparency temporarily, but eventually, the conjunctival cells begin to invade and resurface the cornea. The . . .
Journal Article