Therapeutics
Table 1: Some incurable diseases and their associated deficient cell types DISEASE Diabetes mellitus Myocardial Infarction Stroke
TRAUMATIC BRAIN INJURY Parkinson’s disease
Alzheimer’s disease DEFICIENT CELL TYPE cells Cardiomyocytes Neurons NEURONS Dopaminergic neurons Neurons
Ideally, deficient cells are replenished in situ upon the treatment of therapeutics, eliminating the need for cell transplantation. There may be several approaches capable of accomplishing this. One way is to stimulate adult stem cells to produce the deficient cell type. Another way, which we call in vivo cell reprogramming or IVR, is to directly con- vert another type of cells nearby to the deficient cell type. The IVR approach potentially has a broader application, since the targeted somatic cells are more abundant than adult stem cells.
traditionally incurable diseases are listed in Table 1. A common feature of these diseases is that they are characterised by a deficiency or depletion of particular cells.
Potential treatments for these diseases include drug-based therapies and cell-based therapies. However, both have their limitations. Drug-based therapies usually treat the symptoms of disease only and make the patient chronically dependent upon them. Cell-based therapies are hampered by the scarcity of the source, immune rejection, sub- stantial manufacturing and distribution costs, and high risks in development and commercialisation (Table 2).
Is there an approach that can combine the advantages of both drug-based and cell-based ther- apies while avoiding the shortcomings of both?
Model and mechanisms The aim of in vivo cell reprogramming, also known as in vivo direct reprogramming or in vivo lineage reprogramming, is to achieve the 4Rs – cell regen- eration, replacement, repair and rejuvenation: the holy grail of regenerative medicine. To further dis- cuss IVR, it is first necessary to establish a working terminology for the field. Borrowing terms from enzymology, we named the starting cells we wish to reprogramme substrate cells and the repro- grammed cells product cells (Figure 1). Substrate cells are a cell type that is abundant and in proximity to, or within the affected organs. They should be phylogenetically very close to product cells’ lineage. These three criteria – abun- dance, proximity and relevance – not only make the reprogramming easier, but also ensure that the newly created product cells function similarly to the original cells in the same microenvironment and in response to the same physiological signals. For example, hepatocytes or pancreatic acinar cells (substrate cells) can be converted to pancreatic
Table 2: The limitations of drug-based therapies and cell-based therapies CONVENTIONAL
DRUG-BASED THERAPIES MODALITIES LIMITATIONS Small molecules, proteins, RNAs... Some diseases are untreatable Treat or manage symptoms only Chronic dependence on drugs Expensive
Cells (including stem cells or their derivatives), tissues or organs
Scarcity of donors Immune rejection Unsustainable business models
– Manufacture and distribution costs – Regulatory risks – Development risks – Avoided by investors
82 Drug Discovery World Summer 2011
CELL-BASED THERAPIES
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