N&V 110.pdf - NSPKU

More documents

Recommendations

Info

NEWS AND VIEWS-ARTICLE... the gene into hepatocytes or other tissues and to restore phenylalanine metabolism. This research has been greatly facilitated by the availability of the PKU mouse for testing gene transfer methods. After many years of work, recent experiments in the PKU mouse have produced the most promising results yet. But enthusiasm for these recent successes is tempered by less than stellar results in the few gene transfer clinical trials that have been attempted in humans. The primary site of phenylalanine metabolism is the liver, so the liver is the natural target for gene transfer. However, PAH enzyme is also produced naturally in kidney and pancreas; transfer of the Pah gene into these tissues or even tissues that don’t normally contain PAH might lead to improved phenylalanine metabolism and lower blood phenylalanine levels. In my laboratory, we have explored the possibility of producing PAH enzyme in skeletal muscle or in bone marrow in the PKU mouse, while the research teams of Dr. Beat Thöny in Switzerland and Dr. Thomas Jensen in Denmark have worked to produce PAH in skin cells. All of these approaches have been hampered by an inadequate supply of tetrahydrobiopterin (BH4, the vitamin required for PAH activity) in the target tissues. Work continues to overcome this obstacle, but to date, these approaches have not resulted in a permanent cure in the PKU mouse. Inserting The Gene With Viruses The most promising results have come from gene transfer experiments that target the liver. The liver naturally produces its own BH4, so its supply will not limit the effectiveness of gene therapy. Several different methods for transferring genes into liver cells exist, but the most successful attempts have used Nature’s own method for injecting genes into cells: infection with a virus. Viruses naturally infect cells and carry in their own viral genes. After the virus penetrates into a cell, the virus uses the biochemical machinery of the host cell to make multiple copies of itself. In the final step, the newly formed virus particles break out of the host cell, sometimes killing the host cell in the process, and then continue on to infect other cells. To use a virus as a vehicle for transferring therapeutic genes into cells, many of the normal viral genes are removed and replaced with the therapeutic gene. These altered viral particles are still capable of infecting cells, but because crucial virus genes have been removed, they cannot replicate themselves or produce new infectious virus particles. Adenovirus is a highly infectious virus that causes the common cold. Adenovirus is capable of infecting almost all tissues of the body and is quite effective in penetrating liver cells. Adenovirus vectors that have been altered to carry therapeutic genes have been one of the most commonly employed liver-directed gene transfer methods. Researchers in Dr. Savio Woo’s lab designed an adenovirus vector that carried the human Pah gene and injected this virus into the liver of the PKU mouse (Fang 1994). Liver PAH activity was restored in treated mice by 4 to 7 days after injection of the virus, but the amount of PAH activity varied between 5-20% of normal. Blood phe levels were completely corrected to normal in the animals that had more than 10% PAH activity. Unfortunately, blood phe began to slowly rise in all treated animals and had returned to pretreatment levels by 2 weeks after virus injection. Repeating the treatment had no effect on blood phenylalanine levels. The immune system in mammals has evolved to quickly detect and destroy invading viruses. The treated PKU mice had developed a very strong immune response to the presence of the virus which destroyed the infected liver cells and eliminated the PAH enzyme. Following a second virus injection, the immune system immediately recognized the invading virus and eliminated it before it even had a chance to infect the liver. Injection into the liver of a similar adenovirus vector has actually been used in a human clinical trial designed to treat ornithine transcarbamylase (OTC) deficiency, another inborn error of amino acid metabolism. That trial was stopped because of a similar problem with an immune reaction to the virus. Jesse Gelsinger, an 18 year-old man with OTC deficiency, received a large dose of an adenovirus vector that had been engineered to carry the OTC gene. Within hours of the infusion of the virus into the liver, signs of liver damage began to appear. All evidence pointed to a direct toxic effect of the virus. Jesse eventually lapsed into a coma and died of complete liver failure. During the course of laboratory evaluation of adenovirus, a new type of virus was discovered. This previously unknown virus was found to be contaminating many adenovirus cultures that had been prepared from infected human tissues. This new virus is now called adeno-associated virus (AAV). Since the initial discovery of AAV, eight different subtypes of AAV, all differing slightly from each other and found in different mammals, have been described. AAV can infect many different tissue types but it cannot replicate itself unless an adenovirus has also infected the same cell. AAV by itself does not multiply within cells, kill the host cell, Continued on page... 14 12 News & Views Issue 110
Variety for Life from SHS Biscuits Breakfast Cereals Breads Egg Replacers Milk Replacers Mixes Pasta SHS continues to combine innovation with the latest research to design state of the art formulae for the nutritional management of PKU. The SHS Loprofin and Juvela Low Protein product range offers a choice of tasty, convenient phenylalanine free protein foods and snacks designed for ease of use to people on a PKU diet. • Comprehensive product range • Continued excellence in customer service • 40 years of experience in diet and PKU Contact the SHS Advice Line on 0151 228 1992 or visit our website at www.shsweb.co.uk Low Protein SHS International, 100 Wavertree Boulevard, Liverpool L7 9PT.
Page 1 and 2: Inside this issue... Eh Up Fundrais
Page 3 and 4: Contents 2 NSPKU Prize Winners 4 Eh
Page 5 and 6: NEWS AND VIEWS-REPORTS... NEWS & VI
Page 7 and 8: NEWS AND VIEWS-REPORTS... Bobbies o
Page 9 and 10: Letters News & Views, 51b The High
Page 11 and 12: NOW AVAILABLE ON PRESCRIPTION NOW A
Page 13: NEWS AND VIEWS-ARTICLE... 50% repop
Page 17 and 18: New Loprofin Lasagne sheets are jus
Page 19 and 20: MANUFACTURERS HINTS & TIPS Fate Spe
Page 21 and 22: NEWS AND VIEWS-ARTICLE... London sa
Page 23 and 24: FROM YOUR DIETITIAN... Asda 10 Dark
Page 25 and 26: NEWS AND VIEWS-ARTICLE... you or yo
Page 27 and 28: BIRMINGHAM CHILDREN’S HOSPITAL At
Page 29 and 30: at last a... Ideal for modern day l
Page 31 and 32: NSPKU 32 ND Annual Family Conferenc
Page 33 and 34: CONFERENCE Programme of Events Sat
Page 35: NSPKU Direct Help support NSPKU! We

N&V 110.pdf - NSPKU

Create successful ePaper yourself

Delete template?

Save as template?