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• Response to Leandro C,
• Posted: 2012-01-05 08:45:29 By Michael P
• Hi to All,
  Leandro points out, in a post below, an important change in gene testing for XLRS. There has been talk about the mouse testing for a long time and the details are discussed at http://www.nei.nih.gov/intramural/retinalandmaculardegeneration.asp#3 . It is worth a read and the retina pictures are good. I am hopeful for the young men who will benefit from the gene therapy and am also hopeful for my future grandsons because my daughter is a carrier.
  This is exciting news for our small community of those with XLRS and those who support us.
  Copied from the NEI website: “X-linked Retinoschisis (XLRS) Disease
  Dr. Sieving and his group are investigating the molecular pathology of XLRS disease and are working toward developing gene therapy for this disorder. XLRS is the most common form of macular dystrophy in young males; and there is no effective treatment. All affected males have macular changes, and the majority also present changes in the peripheral retina. The natural history is a slow deterioration in central retinal function. XLRS does not cause outright complete blindness unless there are secondary complications such as retinal detachment or vitreous hemorrhage. The causative gene (retinoschisin, RS1) was identified in 1997, and molecular diagnosis and genetic testing are now available through an affiliated lab. XLRS mutations have been correlated with the disease phenotype. A functional hallmark of XLRS is an electronegative ERG with a markedly reduced b-wave.
  Progress in this research includes creation of RS1 null mice [Zeng, 2004] and the characterization of the long-term history of retinal degeneration [Kjellstrom 2007]. They identified synaptic pathology in RS1 knockout mice—which should provide novel insights into the mechanisms underlying RS1 defects [Takada, 2008]. Study showed the effect of retinoschisin deficit during retinal detachment (in collaboration with Dr. Steve Fisher: Luna, 2009); the characterization of a recombinant viral vector (AAV8-RS1promoterhumanRS1 gene) in preparation for clinical gene therapy; and demonstrated structural and functional rescue of photoreceptors by intravitreal RS1 gene transfer in the XLRS mice. Collectively, these studies form the basis for planning translational work toward a phase-1 human clinical trial by intravitreal administration of the human XLRS gene. An exciting part of the research relates to the demonstration that gene therapy can restore normal ERG responses in the mouse model. Although initial work used subretinal injections to deliver the vector, the Sieving lab has now successfully demonstrated that intravitreal injections using AAV2 vectors are equally effective. Moreover after transfection, high levels of retinoschisin protein expression could be demonstrated in photoreceptors—a surprising finding since previous publications, including Dr. Sieving’s own work, have shown that these vectors normally do not penetrate the outer retina in wild type animals. The demonstration that intravitreal administration of vector is effective in XLRS is likely to have major implications for the ease and safety of gene therapy for human ocular disease in the future. The Sieving laboratory has developed a human clinical trial protocol and has had preliminary discussions with the FDA regarding a phase-1 trial of gene replacement therapy.”
  As always be warned of the dangers and risks in participating in any trials, know that thinks “can get worse”.
  MikeP
  

• X-Linked Diseases
• Posted: 2012-01-05 09:00:55 By Michael P
• Posted from Medline Plus (please visit the page for full details). http://www.nlm.nih.gov/medlineplus/ency/article/002051.htm
  
  "X-linked diseases usually occur in males. Males have only one X chromosome. A single recessive gene on that X chromosome will cause the disease.
  
  The Y chromosome is the other half of the XY gene pair in the male. However, the Y chromosome doesn't contain most of the genes of the X chromosome. It therefore doesn't protect the male. This is seen in diseases such as hemophilia and Duchenne muscular dystrophy.
  
  TYPICAL SCENARIOS
  
  For a given birth, if the mother is a carrier (only one abnormal X chromosome) and the father is normal:
  •25% chance of a normal boy
  •25% chance of a boy with disease
  •25% chance of a normal girl
  •25% chance of a carrier girl without disease
  
  If the father has the disease and the mother is normal:
  •100% chance of a normal boy
  •100% chance of a carrier girl without disease
  
  X-LINKED RECESSIVE DISORDERS IN FEMALES
  
  Females can get an X-linked recessive disorder, but this is very rare. An abnormal gene on the X chromosome from each parent would be required, since a female has two X chromosomes. This could occur in the two scenarios below.
  
  For a given birth, if the mother is a carrier and the father has the disease:
  •25% chance of a healthy boy
  •25% chance of a boy with the disease
  •25% chance of a carrier girl
  •25% chance of a girl with the disease
  
  If the mother has the disease and the father has the disease:
  •100% chance of the child having the disease, whether boy or girl.
  
  The odds of either of these two scenarios are so low that X-linked recessive diseases are sometimes referred to as “male only” diseases. However, this is not technically correct.
  
  Female carriers can have a normal X chromosome that is abnormally inactivated. This is called "skewed X-inactivation." These females may have symptoms similar to those of males."