Closing in on neurological and sensory disorders
Cell-based therapies could be a promising solution in the treatment of neurological and sensory disorders
The numbers are stark. According to the World Health Organization, neurological and sensory disorders (NSDs), such as Parkinson’s disease and Alzheimer’s disease, are set to become the second leading cause of death by 2040. Singapore, while being a young city-state, mimics global trends in terms of life expectancy and the prevalence of NSDs. Currently, an estimated one in 10 people aged 60 and above suffers from an NSD. By 2030, the number is expected to more than double to 103,000. Compounding this problem is the fact that many NSDs are age-related chronic diseases that are non-fatal yet incurable and permanently incapacitating. This places a high disease and economic burden on the patient for the rest of their life.
“Current treatments for NSDs are largely symptomatic, and offer little in terms of restoration of lost tissues and functions. In many cases, long-term drug treatment can lead to adverse side effects. In Parkinson’s disease, for example, long-term therapy with the most commonly used drug, levodopa, is associated with serious motor complications,” explained Associate Professor Lim Kah Leong from NUS Medicine and the National Neuroscience Institute.
“Hence, the prospects for improving prognosis for these diseases remain poor in the near term. We need to achieve scientific breakthroughs that will deliver a cure,” he added.
New strategies, new hope
Given that NSDs are characterised principally by the loss of cells in the retina or central nervous system, cell-based therapies as a neurorestorative strategy represents an intuitive therapeutic approach. By replacing lost or damaged tissues with the appropriate cell type — essentially the basis of regenerative medicine — neural connectivity and innervations can potentially be re-established, thereby providing durable functional recovery and benefits for the patients.
Moreover, the advent of induced pluripotent stem (iPS) cells, which can be generated through a technique developed by Nobel Laureate Shinya Yamanaka, holds promise to revolutionise regenerative medicine. Theoretically, the ability to derive and expand the patient’s own cells via the iPS route can not only help to circumvent ethical issues surrounding the use of stem cells from human embryos or aborted fetuses, but also allow for autologous transplantation to be performed without the concern of immune-rejection.
In reality however, the issue of immune compatibility remains a major obstacle for cell therapy. Although a recipient’s immune response may be suppressed by drugs, their prolonged use can significantly increase the risk of nephrotoxicity, infection and cancer.
“Intuitively, one would propose using patient-specific iPS cells for autologous transplantation to circumvent the issue of immune-rejection. But in the clinical setting, circumstances exist that limits the autologous iPS approach,” said Assoc Prof Lim. “For instance, in patients carrying disease-causing somatic mutations (an alteration in DNA that occurs after conception), it’s necessary to first correct these mutations in iPS cells. This is possible only when the mutations are known and are of a number manageable by existing genome editing technologies, with minimal risks of off-target modification.”
In cases where the mutations have not yet been identified or are otherwise intractable, such as those underlying sporadic forms of diseases such as Parkinson’s disease, a gene correction approach is not feasible. Even when disease-causing mutations do not pose a major problem, background mutations accumulated in adult cells, particularly among the aged, would pose further challenges to obtaining healthy iPS cells. Notably, any attempt to use adult tissues for iPS cell generation would necessarily require the rigorous pre-screening of the source cells or the derived iPS cells for such mutations before they can be used for clinical applications. Furthermore, there are the issues of the time and cost required to produce clinical-grade individualised iPS cells — issues that would put this treatment option out of reach for most patients.
Overcoming these challenges has been the main motivation for Assoc Prof Lim and his team. Not only do they hope to create a safe, stable and renewable source of hypo-immunogenic iPS cells from human umbilical cord lining cells, but they aim to demonstrate utility of these iPS cells for allogeneic transplantation in age-related macular degeneration and Parkinson’s disease; two NSDs that are of national priority.
“We postulate that it is possible to take advantage of the natural phenomena of human umbilical cord lining-derived iPS cells, which are endowed with immunological tolerant properties. This will provide an ideal and readily available source of cells for regenerative medicine,” shared Assoc Prof Lim. “The development of such an ideal cell source will no doubt be a game changer to regenerative medicine.”
The team is currently seeking funding to conduct this work, and to provide the necessary manpower training in the field.