Understanding Gene Therapy in Duchenne

Gene therapy has made significant strides in Duchenne muscular dystrophy, with one therapy approved and other potential therapies in various stages of development.

As our community continues to see progress, many new concepts and terms arise, ones that families have not had to consider before.

PPMD’s resources aim to empower and inform families like yours, providing insights and guidance to help you better understand the dynamic landscape of gene therapy.

We’re here to support you on this journey, offering clarity and knowledge as we navigate this evolving field together.

Approved Duchenne Gene Therapies

ELEVIDYS is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy.

  • This indication is approved under accelerated approval based on expression of ELEVIDYS micro-dystrophin in skeletal muscle observed in patients treated with ELEVIDYS.
  • Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

View PPMD’s resources regarding eligibility and access to ELEVIDYS >

Gene Therapy 101

This 3-minute video provides an overview of the basics of gene therapy in Duchenne.

What is gene therapy?

  • Duchenne is a genetic disorder caused by a variant in the gene that codes for the protein dystrophin. Dystrophin is important for proper muscle function.
  • In Duchenne, the dystrophin gene is dysfunctional and produces little to no dystrophin. This causes muscle cells to become easily damaged leading to loss of muscle.
  • Gene therapy is being developed as a therapy option to treat Duchenne. The goal of gene therapy is to introduce DNA instructions (or transgenes) to cells in the body to treat a disease.

What are the different types?

There are different types of gene therapy, but they all have the same goal – to change the disease progression. This can be done by:

  • Replacing the dysfunctional gene with a functional copy
  • Correcting the disease-causing variant in the gene
  • Introducing a new or modified gene that can help treat the disease
What are the components?

Gene therapy has three important components:

  • The transgene, which is the genetic material being delivered.
  • The vector which carries the transgene into cells. Vectors are usually inactive viruses that will not cause an infection.
  • The promoter which turns the transgene on in specific tissue(s). For example, a functioning copy of the dystrophin gene may be carried by an adeno-associated virus (AAV) and turned on by muscle and/or heart-specific promoters.

What are the limitations?

Like all therapies, gene therapy has limitations, which can include:

  • While gene therapy can be used to slow down disease progression or potentially improve function, it isn’t a cure.
  • How long the benefits last could vary from person to person and depending on the type of gene therapy used.
  • The treatment’s effectiveness may depend on the person’s age and disease stage.
  • Not everyone is eligible to receive gene therapy because it wouldn’t be safe or effective for them. For example, someone who has pre-existing antibodies against the vector cannot receive gene therapy because those antibodies could limit the effectiveness of the therapy and pose safety risks from an immune response.
  • Patients cannot be re-dosed because their body will produce a significant number of antibodies after the initial delivery, so gene therapy is currently a one-time treatment.
  • It is possible that a serious immune response could lead to organ failure or death.

What is the future of gene therapy?

Researchers are working hard to make gene therapy more safe and effective, including exploring:

  • Different vectors
  • Strategies to suppress the immune response

By limiting the immune response, people with pre-existing antibodies or antibodies developed as a result of a previous gene therapy may be able to receive gene therapy in the future.

Video Series 1: Understanding AAV in Gene Therapy

Researchers in Duchenne are currently using an adeno-associated virus (AAV) to deliver the genetic code for dystrophin or other proteins into muscle cells in the body. Learn about the properties of AAV and why it is used, the immune challenges, as well as potential safety concerns.

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Video Series 2: Gene Replacement with Micro-Dystrophin

There are numerous gene therapy strategies in development for Duchenne. Gene replacement strategies with a micro-dystrophin transgene are the furthest along in development and testing and is likely to be an option for a large percentage of people with Duchenne.

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Gene Therapy Trials & Results Data

The tools and resources below provide an overview of what data is available on the gene therapies so far, as well as the currently enrolling clinical trials. It is important to note that this is a rapidly changing area of research, and it is possible that very recent changes or data may not yet be included.

Explore:

Currently Enrolling Trials

This table includes more information about the clinical trials for gene therapies, including the trials that are currently enrolling or expected to begin enrollment.

SponsorCurrently enrolling trialParticipant characteristicsGenetic variant exclusionsPrimary EndpointsPlaceboFollow-upTests RequiredSitesFuture studies
SareptaBy invitation:
ENDEAVOR
46 boys
Uses commercially produced product.
20 boys
  • Initial cohort was 4-8th birthday
  • Stable steroids for 12 weeks
  • Antibodies to AAV are not elevated


Also enrolled boys 8-18 who are ambulatory, boys who are non-ambulatory, and boys age 3. Planning to enroll small number of boys who have variants in exons 1-17.
Microdystrophin levels on Western blot at 12 weeks.None5 years
  • Muscle biopsy
  • Physical exams
  • Laboratory testing
  • Cardiac evaluations
United States: CA, MO, OH, VA
ENVISION 303: Planned to be for non-ambulatory and ambulatory 8-17.
SareptaENVISION

Non-Ambulatory (Cohort 1): 120

Ambulatory (Cohort 2): 28
Non-ambulatory:
  • Non-ambulatory with no age limits
  • Stable corticosteriods (which may include no steroids) for 12 weeks
  • Antibodies to AAV are not elevated

Ambulatory:
  • Ages 8 until the 18th birthday
  • Ability to cooperate with motor testing
  • Stable corticosteroids (which may include no steroids) for at least 12 weeks
  • Antibodies to AAV are not elevated
  • Exclusion of variants in exons 1-17
Change in Performance of Upper Limb score (PUL)Yes, 1:1 with a crossover at 72 weeks.124 weeks (nearly 3 years)
  • Laboratory testing
  • Physical evaluations
  • Muscle biopsy for some participants at certain sites
  • Cardiac evaluation
  • Wearable devices
Non-Ambulatory:
  • Children's Hospital of the King's Daughter, VA
  • Most enrollment to occur outside of the USA

Ambulatory: Will enroll outside of the USA but sites not yet available
GenethonTrial has multiple parts, first is dose finding, second is randomized efficacy.
  • 6-10 years
  • Ambulatory
North Star Ambulatory Assessment (NSAA) scores at 1 year.Yes, in the randomized efficacy part of the study.
  • France
  • England
REGENXBIOAFFINITY DUCHENNE18 boys
  • 4-11 years
  • Stable steroids for 12 weeks
  • Antibodies to AAV are not elevated
  • Functional criteria of walk 100 meters and time to stand
  • Impaired heart function
  • Exclusion of variants in exons 1-17
SafetyNone
  • Muscle biopsy
  • Laboratory testing
  • Physical evaluations such as NSAA
United States: AR
SolidInspire6 boys
Cohort 1:
  • 4-6th birthday
  • Weight less than 40 lbs
  • Stable daily steroids for 12 weeks
  • Antibodies to AAV are not elevated
Cohort 2: 6-8th birthday
  • Exclusion of deletions in exons 1-11 and exons 42-45, inclusive
SafetyNone5 years
  • Muscle biopsy
  • Physical exams
  • Physical evaluations of motor function
  • Lung function testing
  • At home activity monitoring
United States: CA and OH

Current Gene Therapies & Results Data

The table below describes the current gene therapies and gives information so that families can see what they have in common and how they are different. This table also includes very short summaries of results data that have been released thus far, as well as information about side effects.

SareptaPfizerSolid Biosciences
*refers to SGT-003
REGENXBIO
Current Phase of clinical trialsFDA-approved; ongoing Phase 2 and 3 Clinical trials2 and 31/2*1/2
InterventionELEVIDYS
previously known as SRP-9001
(delandistrogene moxeparvovec-rokl)

Recombinant adeno-associated virus carrying a micro-dystrophin gene
PF-06939926 (fordadistrogene movaparvovec)
Recombinant adeno-associated virus carrying a human mini-dystrophin gene
SGT-003
Recombinant adeno-associated virus containing a next-generation micro-dystrophin gene*
RGX-202
nNOS restorationNoNoYes*No
PromoterMHCK7Hybrid muscle specific promoterCK8*Spc5-12, muscle specific promoter
VectorAAVrh74AAV9AAV-SLB101*AAV8
Dose

*Doses in bold are the dose that the company considers effective and is primarily planning to use.
2E14 vg/kgLow dose: 1E14 vg/kg
High dose: 2E14 vg/kg
1E14vg/kg*1E14vg/kg
2E14vg/kg
Route of delivery and frequencyOne time intravenous (IV) infusionOne time IV infusionOne time IV infusion*One time IV infusion
Age range studied (as of December 2023)>2 years2-16 years4-7 years for SGT-003, 4-17 years for SGT-0014-11 years
Total number of boys known to be dosed thus far> 150> 75None dosed yet for SGT-003; 9 were dosed with SGT-0013
Genetic variant limitations in past studiesVariants were required to be within exons 18-58 for the first 4 boys, then all mutations were allowed. EMBARK excluded variants in exons 1-17 and exon 45.None specified in past studies.
Current excluding variants in exons 9-13 and deletions of exons 29-30.
Currently excluding deletions in exons 1-11 and exons 42-45, inclusive*Limiting to variants in exons 18-79.
Data 2020PubMed.gov: 1 year data on the first 4 boys dosed. The data showed no serious adverse events. At one year after dosing, the boys all had functional improvement of NSAA scores and reduced CK compared to prior to treatment. Muscle biopsy showed a mean of 74% of dystrophin on Western blot and 81% of fibers expressing dystrophin. ASGCT 2020: 1 year data on 9 boys ages 6-12, high dose and low dose cohorts. In the 6 boys who had biopsy data at 12 months, mean dystrophin expression (measured by immuno-affinity mass spectrometry) was 24% in the low dose and 52% in the high dose. Mean %positive fibers were 21% in low and 51% in the high dose.
NSAA showed an average improvement of 3.5 points in the 6 boys at 12 months. MRI showed a reduction in fat fraction in the high dose group at 12 months.
Data 2021January 2021 Study 102: Statistically significant increased dystrophin expression (mean of 28% at 12 weeks). Increase in total NSAA score at 48 weeks but not statistically significant. Boys in 4-5 age range did have a statistically significant improvement in NSAA versus the boys on placebo. In the 6-7 boys, the boys on placebo overall had higher baseline NSAA, which may have affected the data analysis.

Jan 2021 Study 101: Three of the initial 4 patients had fat fraction assessment done by MRI through ImagingDMD, independent of the Sarepta study. Minimal fat infiltration was seen compared to boys in natural history studies.

May 2021 on Endeavor: First 11 boys dosed had mean microdystrophin levels of 55% at week 12, with 71% dystrophin positive fibers.

October 2021: Study 101 found that participants (n=4, ages 4 to 7 years) improved 8.6 points on the NSAA compared to a matched natural history cohort three years after treatment. Study 102 found that treated boys (n=12, ages 6 to 7) had a positive 2.9-point difference on NSAA compared to a matched natural history cohort one year after treatment. Study 103 (ENDEAVOR) Cohort 1 (n=11, ages 4-7) found participants improved 3.0 points on NSAA six months after treatment.
MDA March 2021: 19 boys 6-12, high and lose dose cohorts. From 6 boys, NSAA scores were generally improved or stable which was improved compared to an external control group. Starting to enroll non-ambulatory boys.SGT-001 Data (no longer in clinical trial)

MDA March 2021: Muscle biopsies from Cohort B at 90 days showed mean dystrophin of 10%, with %positive fibers 20-70%.

March 2021: Stable NSAA, Mean increase in distance in the 6-Minute walk test, increase in %FVC.

May 2021: 3 boys in Cohort B had biopsies at 12-24 months that showed continued expression (levels of the microdystrophin were below the limit of the test, 70%, and 20%, staying stable or increasing). % positive fibers were at 10-30%, 85%, 50-60%, generally staying the same as the 12 week biopsies.

September 2021: 3 patients at 1.5 years, stability in NSAA, 6MWT, FVC.
Data 2022January 2022: Study 102 participants (n=20, ages 5 to 8) who were initially on placebo and then received gene therapy improved mean NSAA scores by 1.3 points from baseline

July 2022: Study 101 (n=4) patients showed an average of 7 point increase on NSAA over their baseline prior to treatment at 4 years post treatment. Average age of these boys is > 9 years, so their NSAA scores would be expected to be declining.
In Study 103 (n=20), participants improved an average of 4 points from their scores before therapy.
When the 53 patients in 101, 102, and 103 who were dosed the higher dose were combined, at one year after dosing the group had an average NSAA score improvement of 3 points.
MDA March 2022: 19 boys received gene therapy (3 low-dose; 16 high-dose). At one year after dose, NSAA score increased by 1 point, in comparison to an external control cohort (placebo trial participants of similar age, weight, baseline function, and stable steroid use) who had a 4-point decline.

In 14 participants receiving high-dose gene therapy, mean minidystrophin expression at 12 months was 40%, with %positive fibers of 62%.
SGT-001 Data (no longer in clinical trial)
March 2022: Data from the first three high-dose participants suggest improved muscle and lung function at 2 years after the dose. Muscle biopsy data from 3 most recently diagnosed patients show microdystrophin levels similar to what was seen in cohort B at 90 days after dose.
Recruitment opened January 2023
Data 2023November 2023: Topline results of the EMBARK study at 52 weeks did not meet the primary endpoint (NSAA) but data showed substantial evidence of safety and effectiveness based on secondary endpoints, time function tests.October 2023: At 12 weeks after dosing, muscle biopsy on the first two boys treated showed "robust" microdystrophin expression with microdystrophin present in the muscle cell membrane.
Adverse events notedVomiting, decreased appetite, and nausea were most common.

Of the 84 patients who had been dosed at last data cut, 7 (8.3%) have experienced serious adverse events, which included vomiting and liver injury. An immune reaction causing inflamed muscles, muscle fatigue and weakness (myositis) was seen in one participant, which was thought to be related to the specific genetic change. Another patient had myocarditis, inflammation of the heart muscle.

Side effects required medical interventions including hospitalizations, but did resolve.
Vomiting, dehydration, nausea, sudden kidney injury from an overactive immune response (atypical hemolytic uremic syndrome-like complement activation), low platelets in the blood (thrombocytopenia).

In early trials, interventions were required including hospitalizations, but all resolved. Steroid dosing was altered to increase dose slightly around the time of gene therapy dosing.

Three serious adverse events, including myocarditis or inflammation of the heart tissue, occurred in CIFFREO. Participants with certain genetic variants could be at higher risk for these adverse events, so exclusion of certain genetic variants was recommended.

A participant in the Phase 2 trial who was non-ambulatory died following administration of the gene therapy. Following this death, the CIFFREO study was placed on hold, which has subsequently been lifted following modification. All possible investigations were undertaken to understand this case and avoid similar future events. The protocol was modified to require that participants be in the hospital for one week after receiving the dose.
SGT-001 Data (no longer in clinical trial)
Vomiting, nausea, sudden kidney injury, thrombocytopenia.

Interventions were required including hospitalizations, but all resolved.

Because of Serious Adverse Events, the study was placed on hold from November of 2019 until October of 2020.

Changes were made to the manufacturing process, and additional medicines (Soliris and a C1 esterase inhibitor) were done before the dose. Inflammatory response seen in one boy after the changes were implemented.

Our Understanding of Current Data

Many families ask us which of these gene therapies is the “best”, and the answer to that is that we do not yet know. Because the gene therapies are in clinical trials, we are still gathering data to understand how well they work and how long they last.

  • The data that we currently have suggests that the gene therapies, especially at the current higher doses, result in increased expression of the micro/mini-dystrophin and that the increase lasts for at least a year.
  • Current data also shows that most boys who receive the gene therapy will have side effects. For most, the side effects occur soon after the dosing and are manageable with medications such as steroids and other treatment, and in some cases, hospitalizations.
  • We also know that, tragically, one child died after receiving gene therapy. Details regarding what happened for that child are limited.
  • We also do not yet know how well the micro/mini-dystrophins will function as a replacement for standard dystrophin or how long the production of the micro/mini-dystrophin will last.

Additional Gene Therapy Topics

Dive deeper into in-depth gene therapy topics.

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Gene Therapy Terms to Know

Below are some of the essential terms related to gene therapy and Duchenne.

AAV

Adeno–associated viruses (AAV) are small viruses that can be deactivated and used to transmit gene–based treatments to patients.

Antibody

A protein used by the immune system to recognize foreign material in the body. An antibody can bind foreign material to prevent it from infecting a cell or signal the immune system to attach an infected cell.

Antibody Titer

The measure of how many antibodies a person has for a particular virus. An individual can be tested for the amount of antibodies in the blood that prevent AAV from infecting a cell, i.e. neutralizing antibodies. Alternatively, an individual can be tested for the presence of antibodies that can bind to AAV, though the ability of an antibody to bind a virus does not mean it will prevent the virus from infecting a cell.

Capsid

The outside shell that protects a virus and helps it penetrate a cell membrane. A capsid is a protein coat that surrounds a virus. A capsid protects the contents, and helps the virus attach to a targeted cell to penetrate the cell membrane. In gene editing, the special characteristics of a capsid can enable gene delivery to specific cells.

CRISPR

CRISPR is a gene–editing technique that allows scientists to alter DNA sequences easily and precisely in order to modify gene function. CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats that are a type of DNA sequence in a gene. This type of DNA sequence is understood by scientists who can use molecular tools to modify how the gene functions.

Gene Editing

Gene editing makes targeted changes to existing DNA in genes located on the chromosomes. With gene editing, researchers can enable or disable targeted genes, correct harmful mutations, and change the activity of specific genes. Gene editing is a set of techniques that enable researchers and clinicians to rewrite the instruction encoded in the DNA of genes. These molecular–biology techniques can enable or disable targeted genes, correct harmful mutations, modify expression of genes or change activity of a specific cell, with the goal of restoring normal function. CRISPR is an example of a gene editing technique.

Gene Therapy

Gene therapy is a technique that modifies a person’s genes to treat or cure disease. Human gene therapy seeks to modify or manipulate the expression of a gene or to alter the biological properties of living cells for therapeutic use. Gene therapies can work by several mechanisms:

  • Replacing a disease–causing gene with a healthy copy of the gene
  • Inactivating a disease–causing gene that is not functioning properly
  • Introducing a new or modified gene into the body to help treat a disease

Gene therapy products are being studied to treat diseases including cancer, genetic diseases, and infectious diseases.

Genes

Regions of DNA that direct the production of proteins that are the building blocks of our bodies. Genes are inherited from our biological parents. Defective genes can result in a disease or medical disorder. Genes direct biologically important functions throughout the body. Mutations, or errors, in genes can cause disease by failing to produce sufficient levels of a functional protein.

Neutralizing Antibodies

A type of antibody that binds foreign material, like a virus, and prevents it from infecting cells.

Pre-existing Antibodies

Antibodies to a specific virus that an individual has been exposed to and the immune system has developed antibodies to prevent future infection.

Promoter

A sequence of DNA that controls where in the body the transgene is expressed or turned on.

Serotypes

Different variations of viruses. Adeno-associated virus has many serotypes being tested in clinical trials. Serotypes can be naturally occurring variations or modified versions created by researchers. Antibodies to one serotype may still retain the ability to neutralize another variant.

Transgene

The genetic material being delivered to modify, replace, or restore gene expression to begin producing protein.

Tropism

The ability of different vectors to target specific cell types or tissues. A tropism is the natural attraction of a virus or vector to receptors present only on certain cells or tissues. Gene therapy researchers exploit tropisms to help different viruses, lipid particles, or other therapeutic carriers reach their targeted cells.

Vector

Modified virus, cells, or nanoparticles that shuttle the transgene and promoter DNA sequences into the cells of the body.