The near-term potential of stem cell therapies

The prospect of therapies based on human stem cells holds great promise for revolutionising the practice of medicine, says Silviu Itescu.

There are two types of stem cells, those obtained from embryos and those obtained from adults. For a variety of reasons, adult stem cells are more likely to return earlier therapeutic and financial returns on investment than embryonic stem (ES) cells.

Here, I consider the current status and future prospects of the field from the perspective of a clinician undertaking translational research.

The issues with ES cells

Although ES cells offer great scope for fruitful research, the ethical issues surrounding their access and use pose major problems for many members of the community. These issues have provoked considerable debate around the world in recent years and may be insoluble.

In addition, being less mature, ES cells require many more steps in differentiation than adult stem cells to reach the functional, desired cell type for tissue repair.

Finally, and perhaps of the greatest concern, ES cells, with their extraordinary ability to grow, divide and differentiate into any type of adult cell, carry a major risk of causing cancer. No such risk has been identified for adult stem cells.

For these reasons, it is extremely unlikely that ES cells will lead to a commercial product in the foreseeable future, while the use of adult stem cells sidesteps each of these concerns.

Adult stem cells in therapy

I approached the area of stem cell research from a clinician's perspective. In my role as director of transplant immunology at Columbia University Medical Centre in New York, I see patients in desperate need of heart transplantation who have nowhere to go for effective therapy.

Donor organs are in short supply and while artificial devices may be appropriate for some end-stage heart failure patients, they will never be able to meet the ever-increasing needs of the large numbers of patients with ischemic heart disease and heart failure.

In 2001, my group at Columbia University was the first to show that human adult stem cells could be used to repair a damaged heart.

As a result of our published work, numerous clinical trials using various types of human adult stem cells have been initiated, and the field currently holds great promise for the treatment of cardiovascular disease.

Developing novel therapies

Understanding the commercial potential of this type of therapeutic approach, I established Angioblast Systems in New York in 2001 to develop novel therapies for patients with cardiovascular diseases based on adult stem cells and other biological technologies.

Key to commercialisation of an adult stem cell therapy for cardiovascular diseases is the need for a technology that is potent, efficient and amenable to scale-up, accessible to the clinician, and that can compete commercially within the pharmaceutical industry.

Through my worldwide collaborative relationships, I identified a technology that met these requirements that had been developed over more than 10 years by Paul Simmons, Stan Gronthos and Andrew Zannettino, world-leading scientists at the Hanson Institute and the Institute for Medical and Veterinary Sciences (IMVS), in Adelaide, South Australia.

The IMVS had filed patents covering the identification, isolation, expansion and use of mesenchymal precursor cells (MPCs), a type of adult stem cell found throughout the body.

In contrast to the haematopoietic type of adult stem cells, which can only generate blood cells, MPCs can be used to generate a wide variety of tissues, including large calibre arterioles, heart muscle, bone, cartilage and fat.

In addition, MPCs can be easily expanded in vitro, and have the unique property that they are not recognised as foreign by the immune system of unrelated individuals.

This raises the possibility that MPCs may potentially be obtained from universal donors, expanded, and used in multiple unrelated recipients as 'off-the-shelf' products by clinicians.

Cardiovascular, bone and cartilage applications

In 2004, Angioblast Systems acquired the technology outright from the Hanson Institute, with a view to developing the MPCs for cardiovascular applications.

The biology of MPCs is such that they have many other applications in addition to cardiovascular disease. Indeed, the scientists at the Hanson Institute and the IMVS had predominantly concentrated on the orthopaedic potential of these cells, including their generation of new bone and cartilage, and had demonstrated that MPCs could be used to repair large defects in long bone fractures of sheep.

To commercialise an adult stem cell product for the large market opportunities inherent in the orthopaedic applications of MPCs would require a separate funding strategy, separate skill sets, and separate clinical development from those associated with the cardiovascular program of Angioblast. Consequently, Mesoblast was formed to commercialise the MPC technology exclusively for bone and cartilage applications. (The company was successfully floated on the Australian Stock Exchange in December 2004).

The numbers of patients suffering from orthopaedic and cardiovascular conditions that are amenable to treatment with MPCs is staggering.

In the US alone, more than 500,000 patients per year undergo procedures for accelerating bone regeneration and repair in long bones and vertebrae, and more than 800,000 per year undergo arthroscopic procedures for the diagnosis or treatment of cartilage degeneration in the knee.

For these conditions, an MPC-based product that will cause regeneration of bone or cartilage will have broad community impact, both at the level of healthcare costs and patient wellbeing.

Of the one million new heart attack victims treated in the US annually, about 50 per cent will go on to develop chronic heart failure (CHF) due to the residual effects of the damage caused.

Current pharmaceutical therapies for CHF (beta blockers and angiotensin converting enzyme inhibitors) are at best only modestly effective. Gene therapy for blood vessel growth or cardiac repair is a long way off, and associated with major problems related to safety and effective gene delivery.

As with orthopaedic indications, MPC-based therapies would have a major impact on healthcare costs and patient outcomes if a single therapeutic course could prevent the onset of heart failure and long-term deterioration of cardiac function after a heart attack.

Continuing the progress

There are clearly risks along the way to achieving human cardiovascular and orthopaedic therapy based on MPCs.

A major question is whether these cells, which do not activate immune cells in vitro, will induce an immune response in humans. If they do, an alternative approach would be to use a patient's own MPCs.

Other areas of risk include the need to demonstrate sufficient efficacy of MPC treatment, the conditions for delivery of the cells, and cost-effectiveness.

Proceeding cautiously, understanding the risks inherent in any new technology, and being realistic about the limits of the therapeutic potential of that technology, are essential to the ability of a clinician/scientist to pioneer a new therapy successfully.

I have confidence that the approach being taken by both Mesoblast and Angioblast to solving each of these points is sound, with considered pre-clinical and clinical development programs that are likely to lead to timely product commercialisation.

In large part, my confidence stems from the fact that this technology is not at an early stage of development. Considerable progress has already been made in this area of technology over the past decade, by leading Australian scientists.

Prof Silviu Itescu is director of transplant immunology at Columbia University Medical Centre in New York and founder of ASX listed Mesoblast.