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February 2023 fireside chat follow-up

On Sunday February 12th, Alana Newhouse hosted a special edition of “Genes & Juice” with Dr. Allyson Berent, Chief Science Officer and Nycole Copping, PhD, Science Director.

After Allyson and Nycole shared information about the latest pre-clinical work being done in gene and cell therapy advancing potential therapeutics for Angelman syndrome, a question came up around how these different therapeutics would be delivered to humans. This information is very important as families will soon need to be making informed decisions about their loved ones in regards to these types of potential therapeutics. 

Many companies are working on several different promising therapeutic approaches for individuals living with Angelman syndrome. Below is an overview of different delivery approaches for Pillar 1 - gene therapies (e.g. AAV/HSC) or Pillar 2 - disease modifying therapies (e.g. ASOs), depending upon the type of platform.

Pillar 1 - Fix mom’s Gene

Adeno-Associated Virus Gene Therapy (AAV-GT)

  • The brain is protected by a blood brain barrier, which makes it challenging to introduce a gene therapy to the cells of the brain (neurons), which is the cell type that is targeted for Angelman syndrome. Because of this, with the current viral vectors available, AAV-GT needs to be injected directly into the central nervous system compartment (e.g. cerebral spinal fluid [CSF] or brain tissue), in order to bypass the blood brain barrier and cover as much of the brain tissue as possible. This is termed “in vivo” gene therapy because the viral vector is delivered directly into the body.
  • This therapeutic strategy uses an AAV vector to carry a functional copy of the UBE3A gene to the neurons in the brain.
  • There are various approaches that we will be hearing about in the coming months which can help get this virus into the central nervous system of humans to best reach the brain. The specific delivery approach will be decided upon by the different companies working on this type of therapy and none of them have disclosed their preferred method yet:
    • In the spinal fluid that is sitting just behind the base of the skull (intra cisterna magna (ICM)): This is where one would place a needle at the back of the neck, just below the skull and inject the viral vector that is carrying the gene. This will be infused into this pocket of fluid so that it can quickly surround and enter the brain cells (neurons). 
    • In the ventricle of the brain (Intracerebroventricular (ICV)):  This is where one would place a needle into the pocket of fluid that is deep inside the brain tissue called the ventricle. This is done with a needle that must go through a small hole in the skull bone, which will then be directed into this pocket of fluid. This would be carefully guided by imaging like an MRI.
    • Direct brain injection: This is where a needle could be used to enter the tissue of the brain and deliver the viral vector specifically to the tissue and not the fluid. There is some data to support that this approach can give better distribution of the gene therapy throughout the brain and this is being done for other neurologic diseases currently, but not yet for Angelman syndrome. 
    • Lower lumbar spinal tap: This is the approach some companies are taking which is similar to a basic spinal tap at the lower back. This is technically easier to perform but can be a bit more challenging because it is a long way from the brain and much of the viral vector may not make it to the target tissue of the brain, and will instead only get to the spinal cord or be pushed out of the central nervous system to the periphery along the way. 
  • There is typically a trade off between invasiveness of the delivery method and distribution of the therapeutic. There is a lot of work being done to look at which delivery method would provide the best distribution to the deep brain structures and each company will have rationale for the choices that they make. 
  • This type of therapeutic would likely be considered a “one and done” therapy meaning the patient would receive the treatment and then be seen over time for monitoring but would likely not get another dose of the gene therapy. Over time new technologies may make additional treatments possible but for the foreseeable future a patient would not need multiple anesthesia events for re-treatment.

Hematopoietic Stem Cell Gene Therapy using a Lentivirus (HSC-GT)

  • This therapy uses hematopoietic stem cells treated with another viral vector, a lentiviral vector (LVV), carrying a functional copy of a gene. For Angelman syndrome this is UBE3A
  • This therapeutic platform is another type of gene therapy, but instead of an adeno-associated virus (AAV) that is delivered directly into the central nervous system (in vivo), this is a technique where the patients young blood cells are taken out of the body through an intravenous catheter (IV) and then modified with the new gene that needs to be replaced. This is added to the cells using a lentiviral vector (LVV) (ex vivo). This allows the gene to be incorporated into the blood cells, which are then delivered back to the body through the veins (and IV catheter). Space is made in the bone marrow to allow room for these newly modified patient cells expressing the functional gene to incorporate and live there long-term. This space is made using a conditioning regimen that is often a type of chemotherapy.  This is called an autogenous (patient’s own cells) bone marrow transplant. Then, the bone marrow cells containing the new gene travel through the blood and cross the blood brain barrier readily, where they bathe the entire brain.
  • This means that you do not access the brain directly to deliver the gene with any sort of virus because these cells in the bone marrow regularly travel to the brain and sit in the central nervous system. This delivery has wide distribution around all parts of the brain tissue since it crosses the blood brain barrier. 
  • This would be a one time treatment paradigm as well.

Pillar 2 - Turn on Dad’s Gene

Antisense oligonucleotides (ASO) 

  • These are small, synthetic strands of DNA and RNA that bind to specific sequences of RNA. In the case of Angelman syndrome the target is binding to the UBE3A antisense transcript, a piece of RNA that silences paternal UBE3A. The goal of this approach is to turn on the father’s copy of the gene, or “stop the stop”.  
  • This type of therapeutic is delivered through the spinal fluid by a lumbar puncture (LP) or spinal tap in the lower spine. 
  • Generally, ASOs can not cross the blood brain barrier if delivered peripherally (by the blood), therefore they must be injected into the cerebrospinal fluid. However, because of their properties, injecting them into the spinal fluid with a spinal injection results in great distribution to the brain and spinal cord. 
  • There are currently 3 investigational ASOs that are in human clinical trials for Angelman syndrome.
  • This type of therapeutic platform does require multiple treatments because it does not last for years, as is expected for gene therapy.  It is expected one might need an infusion 3-4+ times per year.

For more information on FAST's Roadmap to a Cure 2.0, check out Allyson's talk at the 2022 Global Science Summit on Youtube!