Early detection of lysosomal storage disorders

Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or...

Reexamination Certificate

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C435S007100, C435S007400, C435S007700, C435S007720, C435S007900, C435S007920

Reexamination Certificate

active

06759189

ABSTRACT:

The present invention relates generally to lysosomal storage disorders and to diagnostic agents for their detection in humans and other animals. More particularly, the present invention is directed to the uses of the LSD markers Lamp-1, Lamp-2. Limp-II, 4-sulphatase, acid phosphatase (ACP), &bgr;-hexosaminidase or &agr;-mannosidase, amongst others as diagnostic agents for the detection of many lysosomal storage disorders.
Bibliographic details of the publications referred to in this specification by author are collected at the end of the description.
Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated element or integer or group of elements or integers, but not the exclusion of any other element or integer or group of elements or integers.
Lysosomal storage disorders (LSD) represent a group of 39 distinct genetic diseases, each one resulting from a deficiency of a particular lysosomal protein or, in a few cases, from non-lysosomal proteins which are involved in lysosomal biogenesis. The importance of these disorders to health care becomes obvious when the group incidence rate for LSD (1:5,000 births) is compared with well known and intensively studied genetic disorders, for which newborn screening is currently performed, such as phenylketonuria (1:14,000) and cystic fibrosis (1:2,500). LSD generally affect young children and have a devastating impact on the child and the family involved. Affected individuals can present with a wide range of clinical symptoms depending upon the specific disorder and the particular genotype involved. Central nervous system dysfunction, from behavioural problems to severe mental retardation, is characteristic of many LSD. In the mucopolysaccharidoses, other symptoms may include skeletal abnormalities, organomegaly, corneal clouding and dysmorphic features (Neufeld and Meunzer, 1995). In severe cases, the child requires constant medical management of the disorder but dies before adolescence.
Except for those cases with a family history of the disease, pre-symptomatic detection of LSD can only be achieved by newborn screening. Currently, even after the presentation of clinical symptoms, the diagnosis of a LSD is a complex process involving a range of assays performed on urine, blood and in some disorders, skin fibroblasts. These assays are time consuming, expensive and invasive, making them unsuitable for newborn screening applications. In order to justify the screening of the entire neonatal population for a given disorder or group of disorders there are a number of criteria which need to be satisfied, these criteria can be summarised as two broad considerations. Firstly, does neonatal diagnosis provide clear cut benefits to the neonate and family? Secondly, are these benefits reasonably balanced by the total cost of screening?
In recent years, treatment of some LSD has become possible. Cystinosis is treated with cysteamine (Gahl et al., 1987; Markello et al., 1993), a number of LSD including mucopolysaccharidosis (MPS) I and MPS VI have been responsive to bone marrow transplants (Hoogerbrugge et al, 1995; Hopwood et al, 1993) and Gaucher disease is currently being treated by enzyme replacement therapy which, like bone marrow transplantation, is theoretically applicable to a wide range of LSD. Recombinant enzymes deficient in many of LSD have been characterised and there are now numerous animal models which are being used to evaluate enzyme replacement and gene therapies for these disorders. Animal models currently in use include dog models for fucosidosis (Taylor et al., 1989) and MPS VII (Haskins et al. 1992), cat models for MPS I, and VI (Crawley et al., 1996; Haskins et al, 1992), goat models of &bgr;-mannosidosis (Jones and Kennedy, 1993) and MPS IIID (Thompson et al., 1992) and mouse models for MPS VII (Sands et al., 1994), galactosialidosis (Zhou et al., 1995) and Niemann-Pick disease (Otterbach and Stoffel, 1995). It is probable that within the next 5 to 10 years effective therapies will be available for many of the LSD.
The effectiveness of these therapies, particularly for those LSD involving central nervous system and bone pathologies, will rely heavily upon the early diagnosis and treatment of the disorder, before the onset of irreversible pathology. Animal studies involving bone marrow transplantation in a fucosidosis dog model, which relates predominantly to central nervous system pathology (Taylor et al., 1989) and enzyme replacement therapy studies in an MPS VI cat model (predominantly bone pathology) (Crawley et al., 1996; Crawley et al., 1997) have shown a clear correlation between the age when treatment was commenced and efficacy and that enzyme replacement therapy is effective for the prevention of bone pathology.
A further consideration, critical to bone marrow transplant therapy, is that early diagnosis of the LSD will allow clinicians to take advantage of the window of opportunity presented by the naturally suppressed immune system of the neonate to maximise the chances of a successful engraftment.
Early detection of these disorders has the added advantage of permitting genetic counselling of the parents, with the option of prenatal diagnosis in subsequent pregnancies, and management of the affected child. Accurate techniques for monitoring progress of the treatment regimes are also required.
One common feature of these LSDs is the accumulation and storage of material normally degraded within the lysosome and transported across the lysosomal membrane. It is generally recognised that this results in an increase in the number and size of lysosomes within the cell from approximately 1% to as much as 50% of total cellular volume. However, although the formation of lysosomal storage vacuoles within affected cells is well-known, the process by which lysosomal biogenesis occurs, in particular the nature and role of genes and enzymes which are involved in the process, is poorly understood.
In work leading up the present invention, the inventors sought to identify proteins nucleic acid molecules, oligosaccharides, gangliosides and processes involved in lysosome biogenesis, which are capable of functioning as markers of lysosome storage disorders (hereinafter referred to as “LSD markers”). The LSD markers identified by the inventors have provided for the development of a wide range of diagnostic and therapeutic reagents for the treatment of LSDs in humans and other animals, including the development of procedures to facilitate the presymptomatic detection of all LSDs in a single assay.
Accordingly, one aspect of the present invention provides a diagnostic method of detecting a lysosomal storage disorder (LSD), monitoring the progress of an LSD or the efficacy of treatment of an LSD in a human or other animal patient comprising assaying the level of expression of an LSD marker as defined herein in a biological sample derived from said patient.
As used herein, the term “LSD marker” or similar term shall be taken to refer to an enzyme, protein, polypeptide or other biomolecule or a homologue, analogue or variant thereof derived from the lysosome of a human or other animal, the presence or level of expression of which is associated with the occurrence, development or onset of at least one LSD in said animal. An LSD marker is usually expressed in a cell derived from a patient having an LSD at a level which is different from that observed for a normal individual.
The present invention extends to the assay of an LSD marker for the diagnosis of a wide range of LSDs selected from, but not limited to the list comprising Pompe disease, Salla disease, Gaucher disease, mucopolysaccharidoses (MPS) including MPS I, MPS II, MPS IIIIA, MPS IIIB, MPS IIIIC, MPS IVA, and MPS VI, I-cell disease including ML II/III, Tay-Sach's disease. Fabry's disease, metachromatic leukodystrophy (MLD), Niemann-Pick disease and multiple sulphatase deficiency, amongst others.
Those skilled in the art will be

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