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Kicho, Inc., Quiver Biopharmaceutical and Antisense Oligonucleotide (ASO) Targets for UBE3a in the Treatment of Dup15Q Syndrome

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Celebration, Florida Spring Break 2025

In a previous blog, I ended with a question about whatever happened to the UBE3a studies as I did not hear about any pharmaceutical companies pursuing it.  Well, I found the answer and happy to report that there is a lot of interest from many parties! 

 Dup15q Alliance recently held a gala to raise funds for finding a cure for Dup15q Syndrome at Philadelphia and an angel donor contributed a million dollars, the most raised by a single donor for this organization. This generous donor will match future donations up to the million dollars that they already donated.  The funds will be used to help two new biotech companies working to find ASO (antisense oligonucleotides) for mRNA transcription products of the UBE3a gene duplicated in the 15q 11.5-13.5 region of the syndrome.

  " Antisense oligonucleotides (ASOs) are short, synthetic strands of RNA or DNA designed to bind specifically to complementary RNA sequences. They play a crucial role in modulating gene expression by targeting messenger RNA (mRNA) to alter its function, which can lead to the degradation of the mRNA or inhibition of its translation into protein. ASOs have potential applications in treating various conditions, including genetic disorders, viral infections, and certain cancers, by selectively silencing genes associated with these diseases. Their mechanisms of action include ribonuclease H-mediated decay of mRNA, steric blockage, and modulation of splicing. " -Wikipedia

Two new biotech companies Kicho, Inc.  and  Quiver Bioscience are both recipients of the raised funds from the gala to promote ASO as a potential treatment option for the syndrome.  Many of the leaders of Quiver Bioscience are clinicians and researchers who had been working with people afflicted by Dup15q Syndrome and other neurodegenerative disorders.  Kicho, Inc. was founded by a parent of a child afflicted with Dup15q Syndrome.  How awe inspiring to find parents who redirect their life's goals to meet their children's needs. 

There are multiple genes duplicated in the 15q11.2-13.1 region and preventing translation of the UBE3a mRNA sequence to its protein product may not in and of itself reverse all the symptoms of the syndrome.  Inspired by how ASO's in spinal muscular atrophy completely obliterated the need for use of assistive devices during ambulation in muscular dystrophy patients, researchers at Charles River Laboratories have shown UBE3a directed ASO's completely reduced SUPEP in rat models of Dup15q Syndrome.   One of the challenges a researcher stated was the complete obliteration  all the UBE3a gene products versus modulation of expression to the happy medium where it would compare to that expressed in healthy brains.  “Because Dup15q is a duplication case, where patients unfortunately produce excess protein, the intent is not to eliminate it but to bring it to a normal range,” said Michael V. Templin, PhD DABT, “That is an added twist to this case because it is always easier to eliminate as compared to moderate.”  How will they measure what the right dosing would be? What will they be measuring against?   

If obliteration of all UBE3a gene product becomes an issue why not consider an alternative pathway to normalizing the proteins targested by the ligase?  Since duplication of the ubiquitin protein Ligase in Dup15q syndrome means more proteins are being tagged for degradation, would another alternative treatment option (aside from developing ASO's) be to identify and supplement the tagged proteins so that even though they are degraded more rapidly in the syndrome compared to normal brains, there will still be enough available for the brain to function normally?

There are a number of GABA receptor genes encoded in the duplicated region to consider also which I've discussed in a previous blog. Researchers are looking for drugs that would target theses gene products such as the   GABAa alpha 5 negative allosteric modulator which include basmisanil and an experimental compound being researched by Saniona pharmaceuticals.   Developing drugs that specifically target the duplicated region gives hope for more personalized drugs that zone in on the targeted genes responsible for a particular pathology as well as reduce off target effects.  Improvements in cognition, memory and speech as so critical to support a more independent life for Lucas in the future but my immediate need right now is seizure control because on a very bad day he can have a cluster of up to 15 with added risk of injuries due to accidents from falls, especially from the head drop/ absence seizures.   Kicho has partnered with  Charles River Laboratories to expedite the drug discovery process as quickly as possible. " Charles River Laboratories is a global contract research organization (CRO) that provides comprehensive services to the pharmaceutical, biotechnology and medical device industries.  The company offers services across the entire lifecycle of drug development, including discovery preclinical and clinical research.  They are known for providing laboratory animal modes, preclinical testing, toxicology studies and other services to help companies bring new therapies to market.  Charles River is also involved in supporting regulatory compliance and research to ensure the safety and efficacy of products under development". -ChatGPT 

I always thought drugs went through a long and laborious process which would entail years from academia to big pharmaceutical companies before coming to market but it's wonderful to see companies such as Charles River Laboratories, Kicho Inc. and Quiver Bioscience in conjunction with the latest use of artificial intelligence, computing power and other advanced technological processes can expedite drug discovery and bring it to market as fast and cheaply as possible, albeit as a mom to a 13 year-old son who is growing up way too fast, it is never quick enough. The company makes use of the "least amount of cost impact and maximum use of time,"   In my previous blog, I shared a tidbit for  March's conference where a similar approach to drug discovery for rare diseases is being pursued.   After the preclinical studies are completed, will they sell their compound to bigger pharmaceutical companies that will then carry out the clinical trials in humans and then mass produce and market it to the general public? The human clinical phase may still take years to complete.  And how long will it take for all the regulatory stuff to pass approval?  How fast do they mean when they say fast?  5 years? a decade? I don't mean to sound impatient, but my son is growing up fast and with a blink of an eye he has turned into a pimply teenager and with another blink he will be an adult. 

Per ChatGPT: The translational product of the UBE3a gene is a protein called ubiquitin-Protein Ligase E3A. (This enzyme is responsible for linking ubiquitin to a protein for degradation). This protein plays a key role in the regulation of various cellular process, particularly in the ubiquitin-proteasome system, where it tags other proteins for degradation by attaching small ubiquitin molecules to them.  In the context of brain development and function UBE3a is crucial.  It is particularly important in neurons, where it regulates synaptic plasticity, learning and memory.  Mutations or deletions of the UBE3a gene are associated with Angelman syndrome, while a duplication results in Dup15q Syndrome.  

Ubiquitin plays a crucial role in regulating protein degradation within cells. Ubiquitination is a post-translation modification where ubiquitin molecules are attached to a target protein, marking it for degradation by the proteasomes.  Targeting the ubiquitin-proteasome system has become a strategy for cancer therapy.  Some proteasome inhibitor drugs currently used for chemotherapy and targeted therapy include bortezomib (Velcase), Carfilzomib (kyprolis). Lenalidomide (Revlimid) in particular, works in part by targeting specific E3 ligases, which leads to the degradation of proteins that promote cancer survival albeit not the E3 ligase in the brain which is what would help with Dup15q Syndrome.

There are over 100 different ubiquitin proteasome systems in the human body but no one has found the drug that inhibits the UBE3a gene product encoded in the duplicated 15q region.  It gives me hope, though, that there are several drugs already in the market that target cancer progression using a similar ubiquitin system. If a drug can be found to treat cancer by this route, why not one to treat Dup15q Syndrome?