Tuesday, November 18, 2008

Strategies in fighting AIDS


Few days ago, I blogged about how Perez et al made use of zinc finger nucleases as DNA scissors to get rid of the CCR5 allele within the CD4 T cell, which would confer resistance to the HIV virus. Yet another method exists, which allows gene editing to be made to the CCR5 gene. This is achieved using single-stranded oligonucleotides. These single-stranded oligonucleotides were shown to induce site-specific alterations by activation of DNA repair pathways.

Oligonucleotide-based gene editing has been suggested as an approach to correct genes resulting in neuro-muscular disorders (Bertoni, 2005). Other than single stranded DNA oligonucleotides, DNA/RNA hybrid molecules and double stranded DNA molecules of 100 - 1000 base pairs can be used. The use of microinjection technology allow for the introduction of these genome-altering molecules into the stem cell (Davis).

Unlike current therapeutic approach to correct the defective gene, the trick is to make the CCR5 gene defective which is the opposite, and in doing so, generate a population of HIV-resistant CD4 T cells.

Citations
1) Bertoni C. Oligonucleotide-mediated gene editing for neuromuscular disorders. Acta Myol. 2005 Dec;24(3):194-201.

2) David BR. Genome editing - Its promise and limitations for gene therap. At: http://www.pasteur.fr/applications/euroconf/geneandcelltherapy/22_Davis_abstract.pdf

Saturday, November 15, 2008

Cure for AIDS


The successful transplant of bone marrow by Dr Gero Huetter and followed by the patient's showing no signs of HIV infection might provide some insights into the road to eradicating HIV.


In 2002, it was reported that the Great Ormond Street Hospital successfully attempted gene therapy of a 'bubble' child, who is obviously suffering from SCID. Earlier in June this year, Perez et al demonstrated HIV resistance in CD4 T cells by transciently expressing CCR5 zinc finger nuclease to induce genetic disruption of the CCR5, which provides stable and heritable resistance to HIV virus (Perez et al, 2008). CCR5 is known to be a mediator in the entry of a HIV virus to a T cell. Those with a mutation in the CCR5 are known to be resistant to HIV. The CCR5 zinc finger nuclease provides permanent disruption of the CCR5 allele. Advances have also been made in "gene editing" techniques, which uses zinc finger nucleases.


Perhaps, a possible approach to curing AIDS would be to introduce the zinc finger nucleases to bone marrow cells via gene therapy techniques, transciently expressing these nucleases in order to disrupt the CCR5 alleles. Without the functional CCR5, these altered cells which will be transplanted back into the bone marrow would generate new generations of HIV resistant CD4 T cells.


Citations

1) Perez EE, Wang J, Miller JC, Jouvenot Y, Kim KA, Liu O, Wang N, Lee G, Bartsevich VV, Lee YL, Guschin DY, Rupniewski I, Waite AJ, Carpenito C, Carroll RG, Orange JS, Urnov FD, Rebar EJ, Ando D, Gregory PD, Riley JL, Holmes MC, June CH. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008 Jul;26(7):808-16. Epub 2008 Jun 29

Thursday, October 2, 2008

Benefits of cooperate charity



In a bid to promote industrialization, tax benefits, discounted operating costs and freely available land are being dangled as carrots to entice companies. Companies also participate in charity drives, which provide them with a form of tax relief.





From a public policy planning perspective, it might be worthwhile to consider the benefits of attacting the cooperate sector to partake in charity drives or relief programs through tax reliefs and forms of benefits. Thus, the policy planner can identify a particular area which requires monetary resources, and solicit for the participation of various companies. Monetary resources are not required all the time. Even donated office space, land, equipment, stores and other peripherals can be done in the name of charity towards the community.

The companies will naturally benefit from tax relief and other benefits in exchange for their charity. They will also benefit from the positive image the community has of them, which itself is a form of advertorial.

In the past, charity organisations have always borne the mantle of charitable or relief works. Perhaps, the cooperate segments of the society should also be roped as well.

Saturday, September 27, 2008

A possible cancer immunotherapy approach - Inducing the formation of granulomas

Granulomas are formed when the immune system encounters an antigen it cannot destroy, and as a result, it attempts to isolate the antigen, leading to the formation of a granuloma. A granuloma consists of macrophages, immune cells and a extracellular matrix. T cells are the perpetuator of granuloma formation, secreting cytokines and expressing adhesion molecules.

Non-resectable tumours have always posed problems for cancer patients. Standard treatment of non-resectable tumours include radiotherapy and chemotherapy. Perhaps, it is possible if the immune system can be tweaked to form a granuloma around the tumour mass, isolating it from the rest of the body. More work into the cellular processes of granuloma formation will give us an idea of the physiological mechanisms behind it. A greater understanding behind the mechanisms will perhaps allow us to consider this part of our immune process a weapon in the fight against cancer.

Citations
Sacco RE, Jensen RJ, Thoen CO, Sandor M, Weinstock J, Lynch RG, Dailey MO. Cytokine secretion and adhesion molecule expression by granuloma T lymphocytes in Mycobacterium avium infection. Am J Pathol. 1996 Jun;148(6):1935-48.

Thursday, March 27, 2008

Alternative approach to tackling cancer: B cell therapy


The work of Brendjens et al in retrovirally infecting peripheral T cells thereby transforming them into 19z1+ cells (capable of targeting CD19+ Burkitt lymphoma cell line) marked another approach in cancer therapy. This work demonstrates the possibility of genetically engineering large populations of patient T cells with reactivity towards tumour antigens. Some of the challenges to these approach are the long-term survivalability of the genetically engineered T cells, their ability to home in on tumour sites and establishing a tumour-specific immune response.


Another approach will be to harness the potential of B cells. Like what Brendjens et al did with T cells, the B cells can be virally infected and transformed into cells that are capable of expressing the tumour specific antibodies. Biologics have become notably used in the war against cancer, with avastin, an anti-VEGF antibody, making the headlines in recent times. Thus, the ability to produce anti-cancer antibodies, our body's natural biologics seem to be an attractive proposition. What is so attractive about the use of B cell therapy comes from another intrinsic property of B cells - their ability to present antigens, i.e. they are antigen presenting cells. This means that the B cells are able to augment the adaptive arm of immune response, presenting antigens and co-stimulating T cells in order to direct immune response against the cancer cells. Thus, the possible approach maybe to genetically-engineer the B cells and expose them to tumour antigens. Some of the challenges may be similar to that experienced in T cells, i.e. the ability of the populations of B cells to survive in the body.


Citations

1) Brian Becknell & Michael A. Caligiuri. Cancer T cell therapy expands. Nature Medicine 9, 257 - 258 (2003)

2) Brentjens, R. et al. Eradication of systemic B cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9, 279–286 (2003).

3) Maher, J., Brentjens, R.J., Gunset, G., Riviere, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR /CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).