Bone Marrow Mononuclear Cell Therapy

"Bone Marrow Mononuclear Cell Therapy" is a form of stem cell therapy. There has been a lot of research on the use of stem cell therapy to treat heart attacks, emphysema, as well as stroke. This entry focuses on stroke treatment.

A novel approach to treating stroke has been invstigated by a research group in Germany.¹ The investigators took bone marrow cells from human volunteers, isolated mononuclear cells from it, and used these to treat stroke in rats.

The bone marrow cells were transplanted directly into the carotid artery three days after stroke was induced in the rats. Rat behaviour was tested before stroke, as well as 2, 5, 14, 23 and 30 days after stroke.

Unfortunately, treatment didn't improve recovery compared to non-treated rats. This study was based on previous research focusing on the treatment of heart attack with mononuclear bone marrow cells, and suggests that one therapy can't directly be translated to another disease. However, the fact that researchers waited three days before treating the stroke might also be significant. It is essential that stroke patients are treated as soon as possible after stroking - for strokes caused by blood clots the treatment window is 3 hours after stroke.²

Previous research into treating stroke with bone marrow cells focused on the use of stromal bone marrow cells³ and not mononuclear cells. Mononuclear cells come mostly from red bone marrow, which gives rise to cells associated with the immune system such as monocytes and lymphocytes. In contrast, stromal stem cells come from the stroma which contains a number of cells that create the correct environment for the production of mononuclear cells in the red bone marrow. The bone marrow stroma contains cells like fibroblasts and macrophages, as well as other factors like colony stimulating factor, which all support the differentiation of blood-related cells in the red bone marrow. Therefore the type of cell used to treat stroke might also be of significance.

Even though mononuclear cells did not effectively treat stroke in this study, mononuclear cells have been used with success in the treatment of heart attack ^{4, 5} and emphysema. ⁶

¹ Minnerup et al. Intracarotid administration of human bone marrow mononuclear cells in rat photothrombotic ischemia. Exp Transl Stroke Med. 2: 3. (2010) (doi:10.1186/2040-7378-2-3)

² http://www.ninds.nih.gov/news_and_events/news_articles/stroke_pooled_analysis_030404.htm

³ Andrews et al. Human adult bone marrow-derived somatic cell therapy results in functional recovery and axonal plasticity following stroke in the rat. Experimental Neurology 211: 588-592 (2008).
Source

⁴ Lunde K et al. Intracoronary Injection of Mononuclear Bone Marrow Cells in Acute Myocardial Infarction. New England Journal of Medicine 355: 1199-1209 (2006).
Source

⁵Leblond, A-L et al. Bone marrow mononuclear stem cells: potential in the treatment of myocardial infarction. Stem Cells and Cloning: Advances and Applications 2: 11–19 (2009).
Source

⁶ Cruz F et al. Bone Marrow-derived Mononuclear Cell Therapy Improved Lung Mechanics And Histology In A Murine Model Of Emphysema. Am. J. Respir. Crit. Care Med. 181: A1013 (2010).
Source

Vaccines - Alzheimer's Disease

There are a number of promising vaccines currently being developed for the treatment of Alzheimer's disease.

Alzheimer's disease is associated with the build up of beta-amyloid plaques that cause the degradation of nerve cells. Most treatments are aimed at preventing the formation of plaques, or breaking up plaques that already exist.

AFFiRiS AG is an Austrian company that has recently entered its Alzhemier's vaccine, AD02, into phase II trials.¹ This means that the vaccine will be used on a large group of human volunteers, as previous small-scale trials have shown positive results. AD02 works by identifying and attacking Alzheimer-related beta-amyloid plaques, and breaking them up.

A group in India has developed an alternative vaccine which they claim is safer than current vaccines,² as it is based on a synthetic form of beta-amyloid, while antibodies can still identify it, and prevent the build up of plaques.

A large collaborative research group in Ohio, USA, has studied the usage of a specific peptide both before the onset of Alzheimer's disease, and after.³ The peptide is similar to a specific part of the plaque-forming beta-amyloid, and therefore induces the immune system to make antibodies specific to these proteins. The group suggests that this peptide provides a much safer alternative to current vaccination strategies.

The usage of DNA in a vaccine that might prevent and treat Alzheimer's disease has also been investigated.⁴ Researchers at the University of Texas studied the effect of vaccinating mice with DNA. The DNA causes the production of beta-amyloid in the mouse which triggers the mouse's immune response against the Alzheimer-causing forms of beta-amyloid. Therefore these mice would have better defence against the onset of Alzheimer's disease, since their immune systems will have been primed against it.

And finally, a totally different approach has been taken by the group of Tsuneya Ikezu at the University of Nebraska. Instead of using beta-amyloid in a vaccine, they've studied the usage of a signalling molecule that plays an important role in controlling inflammation.⁵ This molecule, interleukin 4, plays an important role in immune response. In mice models it was shown that increased levels of interleukin 4 was associated with a decrease in beta-amyloid plaque formation and an increase in nerve cell growth. It also improved spatial learning, showing that it supports brain function.


¹ Press release from AFFiRiS AG
Source

² Subramanian S et al. Design and development of non-fibrillar amyloid β as a potential Alzheimer vaccine. Biochemical and Biophysical Research Communications 394: 393-397 (2010).
Source

³ Wang CM et al. Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer's disease. Neurobiology of Disease 39: 409-422 (2010).
Source

⁴ Qu BX et al. Analysis of three plasmid systems for use in DNA Aβ42 immunization as therapy for Alzheimer's disease. Vaccine 28: 5280-5287 (2010).
Source

⁵ Kiyota T et al. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. doi: 10.1096/fj.10-155317 (2010).
Source

Vaccines - HIV

There are two disease on which a lot of vaccine research is being done - HIV and Alzheimer's disease. This entry will look at the former.

HIV/AIDS

A US-based group from the Baylor Research Institute has patented a vaccine¹ that uses a human antibody to which a small piece of viral protein is attached. In particular, they've produced two variants of this vaccine using two different viral proteins. The combination of antibody and antigen will stimulate the body to produce antibodies aimed at the HI virus.

Another group has done research on the usage of a lentiviral vector as an HIV vaccine.² The lentiviral vector is transferred into cells in the body and produces non-harmful proteins from the HI virus. The human body recognises these proteins as foreign and produces antibodies against the virus.

At the 16th International Symposium on HIV and Emerging Infectious Diseases in France the development of a therapeutic AIDS vaccine was presented.³ This vaccine, V-1 Immunitor, is an oral pill prepared from HI viral proteins (antigens) that have been heat-inactivated. HIV-positive patients who took these oral preparations showed an increase in white blood cells, decreased viral load, increased body weight, and extended survival. These results, obtained in Russia, reflected previous results obtained in Thailand.


¹ (WO/2010/009346) HIV VACCINE BASED ON TARGETING MAXIMIZED GAG AND NEF TO DENDRITIC CELLS
Source

² Lemiale F et al. An HIV-based lentiviral vector as HIV vaccine candidate: Immunogenic characterization. Vaccine 28: 1952-1961 (2010)
Source

³ Bourinbaiar A et al. Pilot trial of oral therapeutic HIV vaccine, V-1 Immunitor, on HIV and HIV/HCV patients in Russia. Retrovirology 7 (Suppl 1): 30. (2010)
Source

Stroke treatment

Granulocyte colony stimulating factor (G-CSF) is a molecule that carries a signal to the bone marrow, causing it to produce granulocytes and neutrophils (types of white blood cell), as well as stem cells.

Researchers have recently found that G-CSF can cause the growth of neurons (nerve cells - such as those in the brain) in young animals. A lot of scientists disagree whether neurons can grow in adult animals (or humans), and believe that damaged brain cells or other neurons cannot be replaced. However, a study¹ has shown that treatment with G-CSF after a stroke improved recovery in aged rats. Treated rats survived better and showed greater improvement in mobility and memory. The scientists observed an increase in a number of neurons, which shows that neurons can be "born" even in adult animals.

This research points the way towards more effective treatment of stroke victims, and could mean an improved prognosis for many stroke patients in the future.

¹ Popa-Wagner A et al. Effects of Granulocyte-Colony Stimulating Factor After Stroke in Aged Rats. Stroke 41:1027 (2010).
Source.

Spinal cord injury

A study funded by the Korean Government has found that neural stem cells can be genetically modified to transfer therapeutic genes to a damaged spinal cord. ¹

The scientists introduced a gene that makes ventricular endothelial growth factor (VEGF) to some neural stem cells in the lab.

The neural stem cells that expressed VEGF were injected into the damaged spinal cords of rats, and showed that it could cause growth of a number of nerve cells, increase the density of blood vessels in the area, enhance tissue sparing, and improve the recovery of mobility in injured rats.

VEGF has been studied to treat heart-related disease for quite some time now, but this study identifies a new way of applying it. It points the way to potential treatment for people with spinal cord injuries.

¹Kim HM et al. Ex Vivo VEGF Delivery by Neural Stem Cells Enhances Proliferation of Glial Progenitors, Angiogenesis, and Tissue Sparing after Spinal Cord Injury. PLoS ONE 4(3): e4987. doi:10.1371/journal.pone.0004987.
Source