Gene Therapy

Used to treat spinal muscular atrophy which is caused by a deletion or loss of function mutation of the SMN1 gene resulting in a defective or missing SMA protein. To solve this issue, The SMN2 gene can be targeted. SMN2 is homologous to SMN1 and is nearly identical to SMN1, except that due to different splicing, it is missing exon 7 leading to a shorter protein. This is due to a C-to-T exchange in exon 7. Nusinersen is an antisense oligonucleotide (DNA/RNA that can bind to a specific RNA sequence) that can modulate alternitive splicing of the SMN2 gene, by inhibiting splicing factors. This causes the integration of exon 7 into the SMN2 mRNA, thus producing full-length SMA protein.
Nusinersen needs to be administered intrathecally (into the spinal fluid) and is given 3 times a year after 4 initial loading doses.

Used to treat spinal muscular atrophy which is caused by a deletion or loss of function mutation in the SMN1 gene. The medicine is made of a DNA sequence identical to a healthy SMN1 gene with a promotor, also known as a transgene. This sequence is put into a adeno-associated virus 9 (AAV9), where the DNA of the virus has been removed, i.e. has been turned into a viral vector.
The medicine is administered intravenously and given only once to children under the age of 2. As the virus enters the blood stream it travels throughout the body targeting the motor neurons. The SMN1 transgene is then inserted by the virus into the nucleus of the motor neurons after having been absorbed into the cells by endocytosis. The transgene then remains in the cells nucleus where it can interact with the native DNA machinery to produce a functioning SMN1 protein. It is important to note that the transgene does not integrate into the DNA of the host.
As this is a virus, the immunesystem will respond by producing antibodies. This is why it is vital to suppress the immunesystem around the time of injection to get the fullest effect of the medicine. This is achieved with corticosteroids. As the AAV9 virus is found naturally in our environment, some children will already have developed an immunity and will therefore not benefit from the infusion.

Used to treat hemophilia A, which is caused by a mutation in the gene F8 which causes a lack of coagulation factor VIII leading to excessive bleeding if injured. The medicine is composed of a DNA sequence nearly identical to the F8 gene with a promotor, also known as a transgene. whithin the transgene the B-domain has been removed and a liver specific promotor added to encourage translation specifically in liver cells. The F8 transgene is injected into an adeno-associated virus serotype 5 (AAV5), where the viruses DNA has been removed, i.e. has been turned into a viral vector. The transgene is then inserted by the virus into the nucleus of the bodys cells after having been absorbed into the cells by endocytosis. This transgene is then expressed in livercells, which leads to increased production and release of coagulation factor VIII into the blood stream.
The medicine is administered intravenously and given only once. As the AAV5 virus is found naturally in our environment, some people will already have developed immunity and will therefore not benefit from the infusion. In patients with severe hemophilia A, this treatment has significantly reduced bleeding and the need for factor VIII concentrate treatment (2022 GENEr8-1 Trial Group).

Used to treat Leber's congenital amaurosis, also known as biallelic RPE65 mutation-associated retinal dystrophy. The medicine is composed of a functional copy of the RPE65 gene with a promotor, also known as a transgene. The transgene is then inserted into a adeno-associated virus serotype 2 (AAV2), where the virus DNA has been removed, i.e. has been turned into a viral vector.
The medicine is administered once in each eye by subretinal injection following a vitrectomy. The virus is then taken up by the retinal pigment epithelium (RPE) cells by endosomes and the virus is then able to bind to the nuclear membrane of the cell and inject its transgene into the cell nucleus. Once the transgene has entered the nucleus, it can utilize the native DNA machinery of the cell to produce healthy RPE65 proteins.