The first program developed by LYSOGENE is for Sanfilippo disease type A, a lysosomal storage disease for which there is currently no treatment.

Genetic diseases:

DNA, or deoxyribonucleic acid is a molecule present in all living cells. DNA contains all the information necessary for an organism's growth and ability to function. The genes present in the chromosomes are made of specific sequences of DNA and form the base unit of heredity. It is the genes that encode the instructions required by our organism to manufacture proteins.



Genetic modifications or mutations are behind a large number of diseases, and cancers in particular. The presence of one or more mutations increases the risk of developing serious neuro-degenerative diseases such as Alzheimer's or Parkinson's disease.

The mutations of a single gene are the cause of the majority of what are known as rare diseases, i.e. diseases that affect less that 5 people in 10,000 according to European criteria, and less than 300,000 people according to criteria in the USA.

In total, rare diseases affect 3 million people in France and more than 30 million in Europe. Of about 8,000 rare diseases identified to date, nearly 80% are of genetic origin and 50% affect children.

Lysosomal Storage Disorders (LSD) :

 

Amongst the rare and serious genetic diseases, there is a particular group of about fifty lysosomal storage diseases (LSD's). These inherited single-gene diseases are linked to a dysfunction of the lysosomal function.

The lysosome is often referred to as the "cellular recycling centre", as it is the compartment responsible for ultimately breaking down constituents that the cell no longer needs. The excess material is broken down by a number of enzymes, which are highly specialised proteins that will sequentially divide the substrate to be eliminated.

The majority of LSD's are triggered when a particular enzyme is either not present or dysfunctional. When this happens, the excess material in question is either not broken down at all or is badly broken down in the lysosome and so they accumulate. Cells will become increasingly full of this excess matter, leading to a dysfunction of the organs concerned.

 

Copyright ©  LYSOGENE

Lysosomal Storage Disorders
Lysosomal storage disorders are hereditary single-gene metabolic diseases characterised by defects in the lysosomal function. This malfunction leads to cellular accumulation of substrate that is not broken down and that leads to the organs concerned dysfunctioning.One of these disorders, Sanfilippo type A syndrome, is due to a deficiency of heparan sulphamidase, a lysosomal enzyme coded by a gene located on chromosome 17. This deficiency leads to an accumulation of heparan sulphate oligosaccharides in all the cells. This accumulation is particularly harmful for the central nervous system leading progressively to altered cognitive functions, multiple handicap and early death.

The LSD's are transmitted by a recessive autosomal genetic defect, except for Hunter (MPSII), Danon  and Fabry disorders which are inherited via the X chromosome. These are rare diseases which each individually affect numbers of people in the order of 1 in 50,000 to 1 in 100,000. This low frequency may however, be much higher in some ethnic groups. Collectively, the occurrence of LSD's is in the order of 1 in 5,000 to 1 in 10,000. These diseases are usually classified according to the accumulated excess matter. Hence, the main categories are sphingolipidoses, mucopolysaccharidoses, glycoproteinoses and type II glycogenosis.

So although each individual lysosomal disease is indeed rare, their cumulative incidence can be considered very high.

Sanfilippo type A disease (Mucopolysaccharidosis type IIIA):

Type A Sanfilippo syndrome (or MPSIIIA) is a rare and fatal lysosomal disease caused by an enzyme deficiency of heparan sulphamidase (SGSH) leading to the accumulation of the mucopolysaccharide, heparan sulphate (Figure 1).

The main clinical symptom is a neurological dysfunction in which affected children have a life expectancy of between 10 and 20 years. There is currently no treatment for the SANFILIPPO syndrome.

This disease, neglected due to the challenges it raises, is the reason behind the founding of LYSOGENE. Indeed, the SAF-301 product, the development of which constitutes the programme at the very heart of the company, is aimed at this pathology.


With SAF-301, LYSOGENE is the first company ever to initiate clinical trials of a gene therapy for the treatment of SANFILIPPO.