Stem Cell therapy has remarkable potential as therapy for Huntington's as well as many other diseases. It brings hope for two types of related treatment: stem cell therapies to repair diseased brain cells and to generate new healthy cells.

But until recently the hope for this type of treatment for Huntington's seemed very far from reality. Now however, with advances in stem cell science and the improved ability to mass produce the millions of cells necessary for every transplant, stem cell therapy is on the move for Huntington's.

Stem Cell Backgrounder

Stem cell definition is straightforward: stem cells are cells that have the ability to renew themselves continuously, and under the right conditions to transform into cells of many different organ types. But then it gets more complicated because there are several types of stem cells that come from different tissue sources, and these types of stem cells possess different abilities.

The National Institutes of Health (NIH) web source provides a primer on Stem Cell Basics. But for purpose of this discussion -- though it is really not this simple -- remember that adult stem cells will be used mostly to repair damaged brain cells, and embryonic stem cells to replace damaged cells.

At present, it isn't known which type of stem cell will be best.

Adult or Mesenchymal Stem Cells (MSC): Much more is known about MSC stem cells. And at present MSC will be the type of stem cells used for clinical trials in the planning stage for Huntington's. This type of cell is most often obtained from bone marrow, but is present in all tissues including fat and skin cells, cord blood and amniotic fluid. These cells can renew and develop into specialized cell types of the tissue or organ. This type of stem cell is also present in the brain, but given a separate name: multipotent neural stem cells (NSC). Both MSC and NSC are the cells are normally activated in response to injury and are responsible for wound healing. During the activation process, MSC cells release BDNF and other chemicals that protect and heal damaged brain cells. Unfortunately NSC cell numbers are too small and their activity suppressed in Huntington's, such that the NSC response to cell injury is inadequate.

The goal of MSC therapy is to transplant millions more of these damage repair cells via a needle injection directly into brain. Until recently this type of transplant therapy was very limited because it had not been possible to produce the vast numbers of cells needed. However after many years of research this barrier has been overcome, and -- using factory-like cell culture processes -- scientists can mass produce huge numbers of high quality MSC stem cells.

And going one step further, scientists have found ways to manipulate MSC stem cells as they are grown in cell culture to produce larger quantities of BDNF and other chemicals that can protect nerve cells [Behrstock S 2008]. This is done by inserting BDNF and other specific genes into stem cells as they are produced. And in very important study, the safety of this type of BDNF-enhanced stem cell transplant has recently been demonstrated in animals [Bauer G 2008].

MSC Stem Cells -- On the Move to People: Large stem cell projects for Huntington's are moving forward at U.C. Davis in California in a program headed by Dr. Jan Nolta, and at the University of Wisconsin led by Dr. Clive Svendsen. Both of these centers are in process of performing studies on Huntington's mouse models with this type of stem cell transplant. Though these results have not yet been made public, both of these sites have plans for first clinical trials in people -- as early as 18 months from now.

Embryonic Stem Cells (ESC): This type of stem cell is derived from embryonic tissue and has greater capacity to generate new cells than MSC stem cells. Accordingly embryonic stem cells are thought to carry greater therapeutic potential -- because in addition to repairing damaged cells, they can form new healthy cells.

In the past transplants utilized for Huntington's patients were obtained directly from fetal striatal brain. And probably because the fetal tissue transplant material often varied -- developmental stage and number of cells transplanted -- results have been quite variable [Kim SU 2009]. However, a recent study from Europe showed that grafted cells from a fetal transplant were beginning to integrate into the human brain and forming new cells as early as 6 months following transplant [Capetian P 2009].

Now that the ban on the use of federal funds for embryonic stem cell research has (at least partially) been lifted, there is greater chance for more rapid advances to be made for this type of cell transplant. Embryonic stem cells can now also be mass produced starting from small amounts of embryonic tissue.

Induced Pluripotent Cells (iPS): This is a method that can circumvent the need for embryonic tissue. iPS stem cells are derived from adult cells which have reverted to cells that have the same characteristics as stem cells derived from embryonic tissue. In this process, scientists insert 4 genes which are normally active in cell development, but are no longer active in adult cells. One of the major concerns is that one of the inserted genes is an oncogene -- or one that is known to promote cancer growth. It appears that this concern may have been mostly overcome: Scientists have found a process that can first add the 4 genes necessary to make stem cells and then specifically remove the added genes when they are no longer needed [Kaji K 2009]. This process should significantly reduce the risk of stem cells causing tumor growth after transplant.

Though it probably has greater therapeutic potential, embryonic cell therapy for Huntington's will need more years of research before human testing. Though the benefits may be very high, the risks of using embryonic stem cell transplants are likely to remain higher than MSC stem cells.

Editor's Comments: Though there is still a lot of work to be done, it is likely that we will see more extensive human testing in clinical trials over the next few years. This type of therapy is very exciting because it has potential not just to treat, but to reverse Huntington's disease both by healing old cells and by supplying new healthy brain cells.

But it is important to remember -- even when our hope is high -- to temper this hope with realism. Stem cell transplants will require delivery directly into brain through a needle that is placed using a stereotactic surgical technique that uses MRI imaging. As with any surgical procedure, this carries anesthesia and surgical risk. Transplant cells will be derived from healthy donors which means that Huntington recipients will need to take drugs lifelong to prevent immune rejection of transplanted cells. And finally, because this type of transplant therapy is new, its long-term risks are unknown. And even if successful, transplants might need to be repeated. Recent studies have shown that mutant huntingtin products can pass through the membranes of a diseased cell to an adjacent normal cell [Ren PH 2009]. At least in Parkinson's this type of mechanism has transmitted disease injury to stem cell graft -- at about 10 years duration [Brundin P 2008].

But bottom-line: Our hopes can be high because the potential for therapeutic benefit is high. And, science and technology might be coming together at the right place to make it happen. Here's hoping it works . .

References

Behrstock S, Ebert AD, Klein S, Schmitt M, Moore JM, Svendsen CN. Lesion-induced increase in survival and migration of human neural progenitor cells releasing GDNF. Cell Transplant. 2008;17(7):753-62. PubMed abstract

Bauer G, Dao MA, Case SS, Meyerrose T, Wirthlin L, Zhou P, Wang X, Herrbrich P, Arevalo J, Csik S, Skelton DC, Walker J, Pepper K, Kohn DB, Nolta JA. In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol Ther. 2008 Jul;16(7):1308-15. doi: 10.1038/mt.2008.93. Epub 2008 May 6. PubMed abstract

Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009 Aug 1;87(10):2183-200. doi: 10.1002/jnr.22054. PubMed abstract

Capetian P, Knoth R, Maciaczyk J, Pantazis G, Ditter M, Bokla L, Landwehrmeyer GB, Volk B, Nikkhah G. Histological findings on fetal striatal grafts in a Huntington's disease patient early after transplantation. Neuroscience. 2009 May 19;160(3):661-75. doi: 10.1016/j.neuroscience.2009.02.035. Epub 2009 Feb 28. PubMed abstract

Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature. 2009 Apr 9;458(7239):771-5. doi: 10.1038/nature07864. Epub 2009 Mar 1. PubMed abstract

Ren PH, Lauckner JE, Kachirskaia I, Heuser JE, Melki R, Kopito RR. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat Cell Biol. 2009 Feb;11(2):219-25. doi: 10.1038/ncb1830. Epub 2009 Jan 18. PubMed abstract

Brundin P, Li JY, Holton JL, Lindvall O, Revesz T. Research in motion: the enigma of Parkinson's disease pathology spread. Nat Rev Neurosci. 2008 Oct;9(10):741-5. doi: 10.1038/nrn2477. Epub 2008 Sep 4. PubMed abstract