Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2000-03-23
2003-03-18
Mosher, Mary E. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
Reexamination Certificate
active
06534259
ABSTRACT:
The present invention relates to a new vaccine/immunisation for the prevention and/or prophylaxis against measles virus infection and to a pharmaceutical or therapeutic composition for the treatment of IBD(Inflammatory Bowel Disease); particularly Crohn's Disease and Ulcerative Colitis and regressive behavioural disease (RBD)(also referred to as “Regressive Developmental Disorder”).
In my earlier Patent Application No. WO 96/30544 I have described how persistent measles virus infection whether of a wild type or vaccine mediated is the origin of some forms of IBD.
The latest and most comprehensive population-based epidemiological studies put the prevalence of IBD in the United Kingdom population alone at 1 in 185 at the age of 26 rising to 1 in 140 at the age of 31. Since prevalence of these diseases increases with age to give a peak onset in the 30 to 35 year age group, this level is due to reach 1 in 80 by the age of 45. This rise is particularly conspicuous in children where the instance of Crohn's Disease has risen by a factor of up to 6 in some areas since 1968.
At present vaccination is used for the prophylactic prevention of measles virus infection and as a public health measure has proved to be generally effective. Infants are injected with an attenuated virus often within the second year of life and lately a booster vaccination schedule has been introduced to all school children approaching primary school age.
Unfortunately as I have shown previously in the above mentioned patent application the use of this vaccine has been shown to be instrumental in development of Crohn's Disease and other forms of IBD over the ensuing 30 to 40 years and particularly has been instrumental in a substantial increase in Crohn's Disease in children since vaccination was started in 1968.
It has now also been shown that use of the MMR vaccine (which is taken to include live attenuated measles vaccine virus, measles virus, mumps vaccine virus and rubella vaccine virus, and wild strains of the aforementioned viruses) results in ileal lymphoid nodular hyperplasia, chronic colitis and regressive developmental disorder including autism (RBD), in some infants. Before vaccination infants were shown to have a normal developmental pattern but often within days to weeks of receiving the vaccination some infants can begin to noticeably regress over time leading to a clinical diagnosis of autism. The MMR vaccine was first used in 1968 and a study in Sweden has shown recently that the prevalence of children with autism has significantly risen. The study has shown that the autistic spectrum of disorders may now affect 1% of the population.
The Physician is therefore confronted with a difficulty at the individual level in that whereas as a public health measure measles vaccination is called for, it can have unwanted effects in those subjects who are unable to immunologically eliminate the virus so introduced.
This is particularly so when there is at present no cure for IBD; sufferers can expect relapses of their disease requiring potent immunosuppressant therapy or removal of the affected bowel and may be condemned to the use of a ostomomy bag. Nor is there a cure for autism; sufferers have to live in a silent world of their own unable to communicate with the rest of the world.
What is needed therefore is a safer vaccine which does not give rise to these problems, and a treatment for those with existing IBD. I have now discovered a combined vaccine/therapeutic agent which is not only most probably safer to administer to children and others by way of vaccination/immunisation, but which also can be used to treat IBD and RBD whether as a complete cure or to alleviate symptoms.
As disclosed in my earlier patent application Crohn's Disease is most probably caused by a failure of the body to completely eliminate the measles virus, probably because of the failure of the initial dosage of virus to illicit a full immune response, which in turn allows the remaining virus to collect at various sites in the body particularly in the small intestine and colon thereby causing the granulomatous vasculitis associated with Crohn's disease.
Although the mechanism of virus infection is not fully elucidated, it seems likely at present that the mechanism which gives rise to gut granuloma is as follows:
Following an incomplete immune response to an attenuated virus challenge in early life, or indeed less often a wild type infection, measles virus collects in the wall of the gut and particularly in the capillaries supplying blood thereto. At some point, often when a patient is between 20 to 30 years old, this induces a vasculitis which in turn causes necrosis of the overlying epithelium of the gut. I have previously shown that measles virus is present in these granulomatous lesions. It appears that for some reason lymphocytes which bind to the measles virus site fail to eliminate the virus so identified. What is needed therefore is a system for “switching on” the destruct mechanisms of the bound lymphocytes which appear to be disenabled by the persistent measles virus particles.
The compositions of the present invention have the ability not only to condition the recipient to raise a specific immune response to MMR and measles virus when used as a vaccine/immunisation, but also to reestablish the appropriate antiviral immune response of an immune system to persistent measles virus infection in IBD.
I have also found that regressive behavioural disorder (RBD) in children is associated with measles, mumps and rubella (MMR) vaccination. Although it is yet to be established which element, if only one of MMR, for example measles virus, is directly implicated, histological and serological examination of a sample of children who exhibited RBD showed lesions in the gut indicative of the problems which arise in IBD and Crohn's Disease. Further I have reviewed a cohort of children who following a period of apparent normality have lost acquired skills including those of communication. These children all have gastrointestinal symptoms including abdominal pain, diarrhoea, and in some cases food intolerance. It is significant that this syndrome only appeared with the introduction of the polyvalent MMR vaccine in 1988 rather than with the monovalent measles vaccine introduced in 1968. This indicates that MMR is responsible for this condition rather than just the measles virus and that accordingly a transfer factor (vide infra) specific for the components other than the measles virus in MMR maybe required.
In these children the mean interval from exposure to the MMR vaccine to the development of first behavioural symptom was six days, indicating a strong temporal association with exposure to the vaccine. Measles virus nucleocapsid protein antigen has been identified with the follicular dendritic cells in areas of lymphoid nodular hyperplasia in the affected intestine, further implicating a causal role for measles virus in this disease. These children exhibit immunodeficiencies associated with reduced numbers of circulating T lymphocytes. Specific boosting of antiviral immunity in these children could, therefore, be expected to be of therapeutic benefit.
Adoptive transfer of non-antigen-specific cell mediated immunity in humans was first demonstrated by Lawrence in Proc.Soc.Biol.Med 1949; 71; 516. This opened a new avenue of research that has led to an increased understanding of the basic immune mechanisms and to the development of many forms of immunomodulant therapy. Lawrence originally showed that transfer of intact, viable, lymphocytes from a normal tuberculin skin test-positive donor to a skin test-negative recipient, resulted in conversion (“transfer”) of the recipient to skin test-positivity.
Lawrence further demonstrated that delayed cutaneous hypersensitivity (DH) responsiveness could be transferred by a soluble, dialysed leucocyte extract (DLE). He termed the factor responsible for this phenomenon “transfer factor” (TF). (TF) could transfer (DH) of a given specificity from a normal skin test-positive
Licata & Tyrrell P.C.
Mosher Mary E.
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