hESC therapy

Current research focuses on differentiating hESC into a variety of cell types for eventual use as cell replacement therapies (CRTs).

Some of the cell types that have or are currently being developed include cardiomyocytes (CM), neurons, hepatocytes, bone marrow cells, islet cells and endothelial cells.

However, the derivation of such cell types from hESCs is not without obstacles and hence current research is focused on overcoming these barriers.

For example, studies are underway to differentiate hESC in to tissue specific CMs and to eradicate their immature properties that distinguish them from adult CMs.

Besides in the future becoming an important alternative to organ transplants, hESC are also being used in field of toxicology and as cellular screens to uncover new chemical entities (NCEs) that can be developed as small molecule drugs.

Studies have shown that cardiomyocytes derived from hESC are validated in vitro models to test drug responses and predict toxicity profiles.

hESC derived cardiomyocytes have been shown to respond to pharmacological stimuli and hence can be used to assess cardiotoxicity like "torsades de pointes".

hESC-derived hepatocytes are also useful models that could be used in the preclinical stages of drug discovery. However, the development of hepatocytes from hESC has proven to be challenging and this hinders the ability to test drug metabolism.

Therefore, current research is focusing on establishing fully functional hESC-derived hepatocytes with stable phase I and II enzyme activity.

Researchers have also differentiated hESC into dopamine-producing cells with the hope that these neurons could be used in the treatment of Parkinson’s disease.

hESCs have also been differentiated to natural killer (NK) cells and bone tissue.

Studies involving hESC are also underway to provide an alternative treatment for diabetes. For example, D’Amour et al were able to differentiate hESC into insulin producing cells.

Use of hESCs in therapy

While an abundance of research on hESC is being carried out in laboratories, only three clinical trials have resulted thus far.

Phase I trials using hESC derived Oligodendrocytes (GRNOPC1) developed by Geron are currently underway in human subjects to treat spinal cord injuries, and Advanced Cell Technologies (ACT) are launching Phase I/II trials in human subjects using hESC derived retinal epithelial pigment (RPE) cells in the treatment of Stargadt’s Macular Dystrophy (SMD) and age related macular degeneration:

Geron has been developing several hESC-derived products to treat spinal cord injury, cardiac and other chronic degenerative diseases.

Currently, one of their products for spinal cord injury, GRNOPC1, is in a phase I clinical trial. GRNOPC1 are oligodendrocyte progenitor cells that were differentiated from hESCs.

In this stem cell process, various growth factors are applied to induce hESCs into oligodendrocyte precursors.

Oligodendrocytes play an important role in repairing the myelin insulation around the nerve cells so that the nerve cells may transmit signals. Upon injection of GRNOPC1 into the spinal cord injury site, restoration of motor and load-bearing functions were significantly improved in rat models.

In 2009, the Food and Drug Administration (FDA) granted Geron clearance for a phase I clinical trial: a multi-center assessment aimed at evaluating the safety and tolerability of GRNOPC1 in patients with complete ASIA (American Spinal Injury Association) Impairment Scale grade A thoracic spinal cord injuries.

Studies were also conducted to further assess the safety and effectiveness of GRNOPC1 in patients affected in the thoracic and cervical regions. However, due to cystic development at the injury site, the clinical trial was put on hold.

New candidate markers and release specifications were subsequently established for GRNOPC1 and the phase I clinical trial resumed in 2010.

Advanced Cell Technology (ACT) is the second company in the United States to begin clinical trials on their hESC-based therapy targeting dry acute macular degeneration (AMD).

Retinal pigment epithelial (RPE) cells in dry AMD degenerate and result in the breakdown of the epithelia in the patient’s macula.

ACT aims to provide treatment to the disease via transplantation of hESC-derived RPE cells. Using a differentiation system free of growth factors and independent of exposure to other cell types, zoonoses-free RPE cells were produced for transplantation.

Significant improvements to visual acuity were observed without any adverse effects in rat models. Like Geron, ACT will adopt a multi-center trial to determine the safety and tolerability of the RPE cells transplanted into patients with dry AMD.

In following trials, ACT aims to demonstrate that these RPE cells will be able to impede the progression of the disease and improve visual acuity in patients.

Given approved phase I/II clinical trial clearance, ACT will also use the hESC-derived RPE cells in a trial for Stargardt’s Disease simultaneously.

A similar proposal to treat AMD with hESC-derived RPE cells is being developed under The London Project, which is expected to begin towards the end of 2011.

These clinical trials represent potential treatments for diseases that have no other treatments.