Variant-Specific Therapies

It is an incredibly exciting time in the Duchenne and Becker muscular dystrophy community with so many potential therapies in the pipeline. Many of these therapies are variant-specific, meaning they will only work for individuals with certain changes (often called variants or mutations) in their Duchenne gene.

This brief explanation may help you to understand if you or your child may be a candidate for one of the variant-specific therapies in development.

If you’ve never had genetic testing or if you need repeat genetic testing, remember that our Decode Duchenne program provides FREE genetic testing to eligible individuals. If you have questions, please contact one of Parent Project Muscular Dystrophy’s board-certified genetic counselors.

Two key types of variant specific therapies

There are currently two types of variant-specific therapies in clinical trials for Duchenne: nonsense variant suppression and exon skipping.

Nonsense variant suppression

Individuals with Duchenne who have a nonsense variant may be candidates for nonsense variant read-through. A nonsense variant is a single change in the Duchenne gene that creates a “premature stop codon”, which basically stops production of the dystrophin protein too early in the process and results in a non-functioning protein. Some (but not all) genetic test reports will state if the variant is a nonsense variant. Learn more about nonsense variant read-through.

Exon skipping

Individuals with Duchenne who have certain “out-of-frame” deletions may be candidates for exon skipping. Out-of-frame deletions usually result in little or no dystrophin protein which usually means the individual will have Duchenne. With exon skipping, one or more of the exons bordering the deletion are also skipped, with the purpose of turning the “out-of-frame” deletion into an “in-frame” deletion. In-frame deletions usually result in some dystrophin protein production. However, the impact that exon skipping will have on an individual’s disease progression has not been clearly demonstrated. Learn more about exon skipping.

Determining if a deletion is amenable to exon-skipping therapies

There are more than 150 different deletions of one or more exons in the dystrophin gene that can cause Duchenne muscular dystrophy. Exon-skipping research is at different stages for many of these deletions. Exon-skipping therapy for some deletions has reached clinical trials. This group includes deletions that are amenable to skipping exons 51, 53, 45, and 44. For other deletions, however, exon-skipping therapy is only theoretical. This group includes deletions that would need more than one exon skipped or that are in specific regions of the gene that may not be correctable with exon-skipping.

If you know your/your child’s genetic change (variant) is an exon deletion, our educational Exon Deletion Tool can help you understand if you/your child may be a candidate for an exon skipping therapy. Table 1 (below) also shows the deletions that would be amenable to the exon-skipping therapies that are furthest in the development pipeline. It does not represent a complete list of all deletions that may be treatable with exon-skipping. If you have questions about your genetic results or variant-specific therapies, contact one of Parent Project Muscular Dystrophy’s board-certified genetic counselors.

Looking to the future: other types of technologies

Researchers are studying other technologies that may provide more variant-specific therapies in the future. One of these technologies is called CRISPR/Cas9. The goal of this technique is to edit the gene itself to correct the variant causing disease. CRISPR/cas9 is being explored for many conditions, but is not ready for clinical trials yet.

Parent Project Muscular Dystrophy offers many ways to stay up to date on research advancements and clinical trials:

• Join The Duchenne Registry
• Browse the Drug Development Pipeline
• Explore Clinical Trials

Table 1: Duchenne gene deletions amenable to certain exon skipping therapies

Exon 51  Skip-amenable	Exon 53  Skip-amenable	Exon 45  Skip-amenable	Exon 44  Skip-amenable	Exon 50  Skip-amenable	Exon 52  Skip-amenable	Exon 55  Skip-amenable
(13% of Duchenne  population)	(8% of Duchenne  population)	(8% of Duchenne  population)	(6% of Duchenne  population)	(4% of Duchenne  population)	(4% of Duchenne  population)	(2% of Duchenne  population)
17-50	19-52	12-44	10-43	20-49	20-51	21-54
19-50	21-52	18-44	11-43	22-49	22-51	23-54
21-50	23-52	44	13-43	51	51	24-54
23-50	24-52	46	14-43	51-53	53	25-54
24-50	25-52	46-47	15-43	51-55	53-55	26-54
25-50	26-52	46-48	16-43		53-57	27-54
26-50	27-52	46-49	17-43		53-59	28-54
27-50	28-52	46-51	19-43		53-60	29-54
28-50	29-52	46-53	21-43			30-54
29-50	30-52	46-55	23-43			31-54
30-50	31-52	46-57	24-43			32-54
31-50	32-52	46-59	25-43			33-54
32-50	33-52	46-60	26-43			34-54
33-50	34-52		27-43			35-54
34-50	35-52		28-43			36-54
35-50	36-52		29-43			37-54
36-50	37-52		30-43			38-54
37-50	38-52		31-43			39-54
38-50	39-52		32-43			40-54
39-50	40-52		33-43			41-54
40-50	41-52		34-43			42-54
41-50	42-52		35-43			43-54
42-50	43-52		36-43			45-54
43-50	45-52		37-43			47-54
45-50	47-52		38-43			48-54
47-50	48-52		39-43			49-54
48-50	49-52		40-43			50-54
49-50	50-52		41-43			52-54
50	52		42-43			54
52	54-58		43			56
52-58	54-61		45			56-62
52-61	54-63		45-54
52-63			45-56
			45-62