Current Pipelines

N=2 Double Exon Skipping: Mice Model ∆6-25 Creation 

As the Executive Director and a Board Member of Hope for Luka inc., I, Tushar Tangsali, am committed to advancing research for Duchenne muscular dystrophy (DMD). 

Our family faces a unique and urgent challenge—our two sons have exon 8-25 deletions in the dystrophin gene, rendering them non-ambulatory. Unfortunately, existing exon-skipping therapies do not apply to their mutation, as they require a double skip of exons 6 and 7. 

Currently, no pharmaceutical companies are pursuing this approach, and gene replacement therapies exclude this mutation due to severe adverse events observed in cases where exons 8 and 9 were absent.

 
 Targeted Start Date April, 10th 2025
Estimated Timeline of ∆6-25 Mice Model Creation March, 31st 2027
Number of Patients Exons 6 & 7 Skipping May Benefit 180 Patients
Total Costs $4,000,000

Likelihood of Positive Results from the 6-25 Mice Model

Existing data from exon 6-18 deletion and exon 6-9 deletion models (PPMD & CureDuchenne Registry in the US, Leiden University Registry in Europe) suggest that the resulting shortened in-frame protein remains functional and stable, leading to a mild Becker phenotype.

Background: Why One-Size-Fits-All Treatments Don’t Work in Muscular Dystrophy

Muscular Dystrophy is caused by mutations in the dystrophin gene— the largest gene in the human body. However, these mutations vary significantly from patient to patient, making it impossible to develop a universal treatment that works for everyone.

The Complexity of Deletions: Why Mutation-Specific Research is Needed

Within deletion-type of mutations, the most common type of mutation, the location and combination of deleted exons varies widely:

  • The dystrophin gene consists of 79 exons, and deletions can occur in many different locations.
  • Some mutations fall within "hotspot" regions, where existing treatments and research efforts are focused.
  • However, many patients have deletions outside of these hotspots, meaning they don’t benefit from current exon-skipping therapies.

Mice Model: To Test the End Result of Exon 6 & 7 Skipping

The primary objective is to test the efficacy of end-result of double exon-skipping that is meant to correct the out-of-frame mutation by skipping exons 6 and 7 (causing severe DMD) and convert them into in-frame mutation, potentially resulting in a milder phenotype with improved mobility and delayed disease progression.

In cases like the Δ8-25 deletion, the absence of exons 6 and 7 could produce a shortened, in-frame dystrophin protein. However, the functionality of this protein is unknown due to the lack of natural occurrences of Δ6-25 deletions. Developing a Δ6-25 humanized DMD/mdx mouse model will allow researchers to assess the therapeutic potential of exon 6 and 7 skipping prior to pursuing the double exon-skipping process.  

The Problem: ∆8-25 deletion Resulting in Severe Duchenne

The screenshot above shows that the shapes of the end of exon 7 and the start of exon 26 do not match, and that is why this is an out-of-frame deletion and a severe DMD.

Possible Solution: Exons 6 & 7 Skipping Research benefitting Large Population of Mutations in the Exons 6, 7 and 8 Hot Spots 

If exons 6 and 7 would be skipped, then we would have a shortened in-frame protein as shown below:
Although this is in-frame, researchers have no idea of how functional and how stable this protein will be because there are no cases in nature with ∆6-25 (exons 6 and
7 are skipped, and 8-25 are deleted). The only way to determine this is to generate a ∆8-25 hDMD/mdx model, and perform the exon 6&7 skipping.

Why Mice Model?

To test the end result before starting exons 6 & 7 skipping Study & Process: 
Instead of developing the ∆8-25 hDMD/mdx model and then testing all the therapies to see if they'll work, we should focus on the end result and work on the development of ∆6-25 hDMD/mdx model. When exons 6 and 7 are skipped, the resultant missing segment will be ∆6-25. If this mouse model shows mild Becker phenotype, then we'll know for certain that the exon-skipping of exons 6 & 7 therapy will become an effective treatment

Current Accessibility of Mice Model Creation for Interested/Active Parents & Patients

  • Current State: 
    • Only Research Facilities/Pharmaceuticals/Universities decide what mice models will be created based on their relevant studies in their pipelines. Parents have no say in that process. 
    • There are no organizations in the world right now offering to create mice models for interested/active parents or patients for their specific mutation.
  • Our Vision To Change That Reality:
    • We are aiming to enable parents, patients, physicians as well as pharmaceutical companies to test the new or already-in-market drugs/trial studies by raising capital for any new mutation that is submitted to our nonprofit, and fund the most credible research facilities to create mice models for each of the mutations.
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