Therapeutic Approaches for Angelman Syndrome
This article has been adapted from the original blog post by Jena Berndt with author’s permission. Information in this article may get outdated as research progresses; it was written in April 2023.
Angelman syndrome is a complex genetic disorder that affects the nervous system. In this article, we will explore various therapeutic approaches currently being advanced for the potential treatment of humans living with Angelman syndrome. We will discuss each method in simpler terms to help everyone better understand what each one means for our loved ones living with this condition.
- Gene Replacement Therapy using Adeno-associated virus (AAV-GT):
This approach involves delivering a healthy copy of the affected gene directly into brain cells, called neurons. This allows these neurons to make a protein that is either missing or not functioning properly. The therapy can be delivered through different methods, such as an injection into the spinal fluid, directly into the brain tissue, or through a vein. There are currently at least seven programs in the pipeline for this approach.
- Gene Replacement Therapy using Hematopoietic Progenitor Cells (HSC-GT):
This method involves putting the affected gene into a patient’s blood cells. These cells can be removed from the patient and modified to carry the new gene, then injected back into the patient. The cells travel through the bloodstream, cross the blood-brain barrier, and release the new gene into the brain. There is currently one program in the pipeline for this approach.
- Antisense Oligonucleotides (ASO) and Spherical Nucleic Acids (SNAs):
These therapies use a combination of synthetic RNA and DNA to bind to a specific RNA molecule responsible for silencing the affected gene in neurons, called UBE3A antisense transcript or UBE3A-ATS. These drugs are designed to “unsilence” the gene, allowing it to function properly. There are currently at least four programs taking this approach.
- Artificial Transcription Factors and Zinc Fingers (ATF-ZF):
This method involves binding the RNA molecule responsible for silencing the UBE3A antisense transcript in a specific area, resulting in the gene being “unsilenced.” Research for this approach is ongoing at UC Davis.
- CRISPR gene editing:
CRISPR is a powerful gene-editing tool that consists of two components: an enzyme that can cut DNA or RNA and a guide RNA that can recognize specific sequences of DNA or RNA to cut. For Angelman syndrome, CRISPR aims to find a sequence in the human genome that could permanently stop the RNA molecule from silencing the affected gene. There are currently at least three programs in the pipeline for this approach.
- Enzyme Replacement Therapy (ERT):
This method involves providing the missing protein directly to the brain. The protein would be modified to enter neurons and function inside and outside the cells. There is currently one program in the pipeline for this approach.
- RNA Interference using short hairpin RNA (shRNA) and microRNA (miRNA):
Both of these therapies introduce an RNA molecule that targets the RNA responsible for silencing the affected gene, activating the gene in neurons. There are currently three programs in the pipeline for this approach.
- Downstream Targets:
This category includes therapies that focus on different molecular pathways and proteins impacted by the missing protein. These drugs generally aim to improve communication between neurons. There are currently at least five different drug candidates in the pipeline for this approach.
In conclusion, there are at least eight different approaches, including 25 programs, being evaluated to potentially treat Angelman syndrome. This gives us hope for a brighter future for all individuals living with this condition. As research continues, we can expect to see more advancements and promising developments in the treatment of Angelman syndrome.
Different Methods of Drug Administration
Various drug administration methods are being explored for the delivery of potential Angelman syndrome treatments, as each therapeutic approach may require a different route of delivery to ensure its effectiveness. Choosing the most appropriate method of administration is crucial, as it can significantly impact the success of a therapy in reaching its target location and exerting the desired therapeutic effect.
One common method of drug administration for neurological conditions is an injection into the cerebrospinal fluid (CSF), which surrounds the brain and spinal cord. This can be done either by a lumbar puncture (injection in the lower back) or through intracisterna magna (ICM; injection at the base of the skull). Both of these methods allow for direct delivery of the therapeutic agent into the CSF, facilitating its distribution to the brain and spinal cord. Another approach is intraparenchymal injection, which involves the direct delivery of a drug into the brain tissue, bypassing the blood-brain barrier and ensuring that the therapeutic agent reaches the target neurons. For some treatments, such as Hematopoietic Progenitor Cell gene replacement therapy (HSC-GT), intravenous injection is used to deliver the modified cells back into the patient’s bloodstream, from where they can then cross the blood-brain barrier and migrate to the brain to exert their therapeutic effect.
In addition to these methods, researchers are also exploring the use of other drug delivery systems and technologies, such as nanoparticles or hydrogels, to improve the bioavailability, stability, and targeting of potential Angelman syndrome therapies. The development of safe and efficient drug delivery methods is a critical aspect of advancing new treatments for Angelman syndrome, as it ensures that these therapies can effectively reach their target sites and provide the desired therapeutic benefits to patients.
Contributions by FAST
The Foundation for Angelman Syndrome Therapeutics (FAST) plays a significant role in supporting and advancing research for potential treatments of Angelman syndrome. FAST is dedicated to funding cutting-edge research programs that have the potential to improve the lives of those affected by Angelman syndrome, with the ultimate goal of finding a cure. They are proud to provide funding for a diverse range of therapeutic approaches, reflecting their commitment to explore every possible avenue to help individuals living with this condition.
FAST has financially supported 16 out of the 25 programs that are currently in the pipeline for Angelman syndrome treatment. This support has been crucial in de-risking these programs and accelerating their progress toward human clinical trials. Among these programs, FAST has funded research on Adeno-associated virus gene replacement therapy (AAV-GT) – 4 programs, Hematopoietic Progenitor Cell gene replacement therapy (HSC-GT) – 1 program, antisense oligonucleotides (ASO) – 1 program, CRISPR – 2 programs, Enzyme Replacement Therapy (ERT) – 1 program, RNA Interference – 1 program, and 4 programs in the Downstream targets group.
FAST’s commitment to supporting the most promising technology and science for the benefit of individuals living with Angelman syndrome has contributed to a sense of optimism within the community. The ongoing research efforts and potential treatments in development offer hope for a future where the lives of those affected by Angelman syndrome can be significantly improved. As FAST continues to invest in these research programs, they are driving progress toward a better understanding of Angelman syndrome and the development of effective therapies.