The State of the Drug Development Pipeline

A therapeutic approach where a healthy copy of a virus, Adeno-Associated Virus (AAV), is used to carry a healthy copy of a gene to a target organ. This is most commonly delivered in-vivo (inside the body). For Angelman syndrome (AS) the healthy copy of the missing or non-functional UBE3A gene is packaged inside the AAV, and is injected into the fluid that surrounds the brain, called the cerebrospinal fluid (CSF). Once in the fluid, the virus and gene can directly reach important cells of the brain, called neurons, and replace the non-functional or missing copy of the gene.

A therapeutic approach where an individual’s own bone marrow stem cells are removed from their body, modified ex vivo, or outside the body, and returned to the body with a replaced copy of the missing or nonfunctional gene (UBE3A in this case). Once the bone marrow cells are injected back into the individual, they go to the bone marrow to grow and repopulate. The goal is for those cells to continuously supply the body with a healthy version of the gene. These cells can cross from the blood to the brain, which is called crossing the blood brain barrier (BBB). Once they cross the blood brain barrier they become a cell type called microglia and secrete the UBE3A protein throughout the brain for neurons to take up the protein and use it.

A gene modulation technology that utilizes a nuclease-deactivated Cas9 protein that binds to the target genomic region with the same efficiency as Cas9, but does not cut the DNA and instead can exert RNA-directed transcriptional control of the targeted gene with a goal to upregulate a specific gene.

Enzyme replacement therapy (ERT) is a medical treatment whereby genetically modified replacement enzymes are given intravenously to patients who suffer from chronic conditions.

A therapeutic approach that uses modified RNA or DNA molecules that bind to the RNA of the UBE3A-ATS (UBE3A antisense transcript). The UBE3A-ATS is responsible for silencing the paternal UBE3A gene through a process called imprinting. In binding to the targeted antisense transcript, the ASO stops the UBE3A-ATS from silencing the expression of the paternal UBE3A gene.

A therapeutic approach that consists of using engineered proteins designed to regulate gene expression in a highly specific manner. They are constructed to bind at specific DNA sequences and can either activate or repress the expression of target genes. ATF-Zinc fingers are small proteins that use zinc ions to stabilize their structures giving them a finger-like appearance. ATF-ZFs can bind to the UBE3A-ATS and prevent the silencing of the paternal copy of the UBE3A gene.

CRISPR is important because it allows scientists to rewrite the genetic code in almost any organism. It is simpler, cheaper, and more precise than previous gene editing techniques.

A low molecular weight compound that is small enough to easily get into tissues, enter cells, and interact with specific biological targets. In AS, small molecules could be developed that function as drugs by modulating biochemical pathways, inhibiting or activating specific proteins, or altering cellular processes shown to be altered in AS neurons. These targets of small molecules can be proteins, DNA, RNA or the ATS.

This therapeutic approach utilizes specific pieces of RNA, called micro-RNA, that are delivered in an AAV virus to the brain, aimed to bind to the UBE3A-ATS and activate the silent paternal copy of the UBE3A gene in neurons.

A therapeutic approach in Angelman syndrome that focuses on different molecular pathways and effector proteins impacted by the missing or non-functional UBE3A protein.

A therapeutic approach where a healthy copy of a virus, Adeno-Associated Virus (AAV), is used to carry a healthy copy of a gene to a target organ. This is most commonly delivered in-vivo (inside the body). For Angelman syndrome (AS) the healthy copy of the missing or non-functional UBE3A gene is packaged inside the AAV, and is injected into the fluid that surrounds the brain, called the cerebrospinal fluid (CSF). Once in the fluid, the virus and gene can directly reach important cells of the brain, called neurons, and replace the non-functional or missing copy of the gene.

A therapeutic approach where an individual’s own bone marrow stem cells are removed from their body, modified ex vivo, or outside the body, and returned to the body with a replaced copy of the missing or nonfunctional gene (UBE3A in this case). Once the bone marrow cells are injected back into the individual, they go to the bone marrow to grow and repopulate. The goal is for those cells to continuously supply the body with a healthy version of the gene. These cells can cross from the blood to the brain, which is called crossing the blood brain barrier (BBB). Once they cross the blood brain barrier they become a cell type called microglia and secrete the UBE3A protein throughout the brain for neurons to take up the protein and use it.

A gene modulation technology that utilizes a nuclease-deactivated Cas9 protein that binds to the target genomic region with the same efficiency as Cas9, but does not cut the DNA and instead can exert RNA-directed transcriptional control of the targeted gene with a goal to upregulate a specific gene.

Enzyme replacement therapy (ERT) is a medical treatment whereby genetically modified replacement enzymes are given intravenously to patients who suffer from chronic conditions.

A therapeutic approach that uses modified RNA or DNA molecules that bind to the RNA of the UBE3A-ATS (UBE3A antisense transcript). The UBE3A-ATS is responsible for silencing the paternal UBE3A gene through a process called imprinting. In binding to the targeted antisense transcript, the ASO stops the UBE3A-ATS from silencing the expression of the paternal UBE3A gene.

A therapeutic approach that consists of using engineered proteins designed to regulate gene expression in a highly specific manner. They are constructed to bind at specific DNA sequences and can either activate or repress the expression of target genes. ATF-Zinc fingers are small proteins that use zinc ions to stabilize their structures giving them a finger-like appearance. ATF-ZFs can bind to the UBE3A-ATS and prevent the silencing of the paternal copy of the UBE3A gene.

CRISPR is important because it allows scientists to rewrite the genetic code in almost any organism. It is simpler, cheaper, and more precise than previous gene editing techniques.

A low molecular weight compound that is small enough to easily get into tissues, enter cells, and interact with specific biological targets. In AS, small molecules could be developed that function as drugs by modulating biochemical pathways, inhibiting or activating specific proteins, or altering cellular processes shown to be altered in AS neurons. These targets of small molecules can be proteins, DNA, RNA or the ATS.

This therapeutic approach utilizes specific pieces of RNA, called micro-RNA, that are delivered in an AAV virus to the brain, aimed to bind to the UBE3A-ATS and activate the silent paternal copy of the UBE3A gene in neurons.

A therapeutic approach in Angelman syndrome that focuses on different molecular pathways and effector proteins impacted by the missing or non-functional UBE3A protein.