The need for more information regarding the role of the system in the progression of the diseases creates difficulty in treating many diseases. This establishes a need for modeling diseases, which helps to develop the treatment for the disease focusing on the major root cause. As genetics play a great role in the biological functions, there were limitations in using the animal models as it exhibited difference between animals and humans.
When the individuals are of different species, there were more complications, as the difference in genetics contributed to different proteins among the two species. So, the animal models could not completely imitate human models. Induced pluripotent stem cells (iPSCs) are good substitute as the approach is different and it can provide similar human cell environment.
Disease modeling and gene therapy
There is a great deal of information which is required to eventually provide better treatment for a disease. Knowing of any existing genetic predispositions for the disease and how these may impact molecular mechanisms to cause the disease phenotype are important.
Below is a list of some diseases in which fibroblasts have been used as source cells and lentiviral integration has been used for the generation of iPSCs.
- Huntington disease (HD)
- ALS or Lou Gehrig's disease
- Friedreich's ataxia (FRDA)
- Shwachman-Bodian-Diamond syndrome (SBDS)
- Gaucher's type III
- Becker type muscular dystrophy (BMD)
- Downs syndrome/trisomy 21
- Familial dysautonomia (FD) or Riley-Day syndrome
- Spinal muscular atrophy
- Type 1 diabetes mellitus (DM)
Parkinson's disease (PD) uses Dermal fibroblasts with idiopathic PD as source cells and lentiviral integration to generate iPSCs.
Below is a list of some diseases in which fibroblasts have been used as source cells and retroviral integration have been used for generation of iPSCs.
- Rett's syndrome
- Hemophilia A
- Hutchinson–Gilford progeria syndrome
- Alzheimer disease
- LEOPARD syndrome
- Timothy's syndrome
- Dyskeratosis congentia
In Childhood cerebral adrenoleukodystrophy (CCALD), skin fibroblasts have been used as source cells and retroviral integration has been used for generation of iPSCs.
Glycogen storage disease 1a, Familial hypercholesterolemia and α1-antitrypsin deficiency use dermal fibroblasts as source cells and retroviral system. In Lesch-Nhyan syndrome dermal fibroblasts are the source cells and lentiviral system have been used.
Application in regenerative medicine
- Conditions such as hematopoietic disorders, musculoskeletal injury, spinal cord injury, liver damage, and the like can be treated by gene therapy of affected cells and tissues by generating specific cells as appropriate to the case from iPSCs.
- Duchhene Muscular Dystrophy (DMD) is a disease that relates to a genetic deficiency in the muscle, and iPSCs have been used to correct the disease and rectify the problem.
- Hepatocyte generation is a common requirement in the treatment of liver problems. Often fetal or adult cells may be required for development of hepatocytes, and there may be either a loss of function of hepatocytes in culture or a limitation in terms of the availability of the organ. iPSCs are a great alternative in such cases.
- Blood and various blood components are required worldwide in the treatment of innumerable medical situations. Various techniques have been evolved for the generation of RBCs and other blood components from iPSCs.
- iPSCs generated from the patient’s cells have been made to differentiate into photoreceptor rod cells or retinal pigmented epithelium and these in turn have been helpful in treating retinal pigmentosa and age-related macular degeneration.
- Certain immunodeficiencies such as chronic granulomatous disorder and Wiskott–Aldrich syndrome have been treated by gene therapy using iPSCs.
- Genome engineering involves the use of a variety of techniques which help in the introduction of various insertions or deletions in target cells. When these are used with iPSCs, they can raise both disease modeling and treatment possibilities to a new level altogether.
Application in drug discovery
Almost all drugs are first studied in animal models or in vitro, using animal-derived cells. The main limitation here revolves around one thing: the inability of the animal system to replicate exactly the physiological conditions and related phenotypic characteristics of the human system. What may be true in an animal system may not always be true in the human system or in another animal system e.g., a chemical that may be toxic to one animal may not be toxic to another animal. All these point to the idea that any new drug be tested on systems closer to humans and, where possible, tested on human cells or human test models.
There is a long time gap and a high cost involvement between the time when a chemical is identified as a potential drug and the actual time it is approved and made available for human use. For these reasons, the development of toxicity models that help in indicating possible hepatotoxic or cardiotoxic effects of drugs long before they are considered for clinical trials may prove a great boon to the pharmaceutical industry. It is because of these factors that iPSCs have been explored by researchers as possible time - and cost-saving alternatives.
Reviewed by Afsaneh Khetrapal BSc (Hons)