Fig. 1: Phenotypic and dysmorphic features of patient 1 (A and B),...
What Does It Mean To Be A Carrier Of Duchenne Muscular Dystrophy?
Duchenne muscular dystrophy (DMD) is a genetic condition that primarily affects people assigned male at birth. However, due to the condition's X-linked inheritance pattern, only people assigned female at birth can be carriers of DMD.
Duchenne muscular dystrophy is a genetic condition that leads to progressive muscle weakness and degeneration. It's caused by mutations in the DMD gene, which carries the instructions for making the protein dystrophin.
Approximately 70% to 80% of people with DMD inherit a genetic mutation that causes the condition from a biological parent who is a carrier. In the remaining 20% to 30% of people, the genetic mutation occurs early on during embryonic development and isn't related to genetics.
A note on sex and genderAt points in this article, we use "female and male" to refer to birth-assigned sex, and "mother and father" to refer to genetic parentage related to birth-assigned sex (unless quoting from sources using nonspecific language).
Birth-assigned sex is typically determined by chromosomes, and gender is a social construct that can vary between time periods and cultures. Both of these aspects are acknowledged to exist on a spectrum both historically and by modern scientific consensus.
To understand what it means to be a carrier of DMD, it's important to understand some baseline genetic patterns.
Typically, people inherit 23 chromosomes from each genetic parent (23 in the egg and 23 in the sperm), resulting in a total of 46 chromosomes. These chromosomes, which are made up of genes, pair together and lay the foundation for fetal development, from physical traits to biological functions.
Within each set of 23 chromosomes from a genetic parent is a sex chromosome — Y or X. The pairing you receive from your two genetic parents determines your birth-assigned sex.
People assigned female at birth typically have the sex chromosomes XX, and those assigned male at birth typically have the sex chromosomes XY. Intersex people may have different combinations of chromosomes, like XXY.
People born with XY sex chromosomes can pass on either an X or a Y, and people with an XX pairing — and no Y — can only pass on an X.
How can people be carriers of DMD?
"Carriers" are people who have one copy of a gene with a mutation that causes a recessive condition like DMD. A person who carries the condition won't show many — or possibly any — symptoms because they have a second, functional copy of the gene.
Recessive conditions typically require a person to have two copies of a mutation to cause the condition. The exception to this are X-linked recessive conditions like DMD, which result from a mutation on the X chromosome.
Because people assigned male at birth typically only have one X chromosome, if a mutation related to a condition is present on that chromosome, the condition fully develops.
People assigned female at birth typically have two X chromosomes. Even if they inherit one X chromosome with a mutation related to DMD, having the other X chromosome without the mutation is often enough to prevent symptoms related to low dystrophin production. This means that only people assigned female at birth can be carriers of DMD.
Each time a person who is a carrier of DMD has a child who is assigned male at birth, the child has a 50% chance of developing DMD. A child assigned female at birth will have a 50% chance of being a carrier.
Genetic testing can analyze the DNA of your cells to screen for known variations in the DMD gene. Geneticists look for known deletions (sections of missing DNA) and duplications (copied and repeated parts of a DNA section) on the DMD gene.
If you were assigned female at birth, testing positive for a mutation known to cause DMD confirms your carrier status.
But, because scientists haven't yet discovered all the DMD-causing genetic variations, it's possible to be a carrier of DMD but not test positive for a genetic variation.
Several reproductive options exist for people who carry a DMD mutation and want to start a family. These options may include having a "natural" birth, which is how some people describe a pregnancy that does not involve IVF.
Natural birth
Being a carrier of DMD does not affect your ability to carry or deliver children. If a person with a DMD mutation gives birth to a child who is assigned female at birth, the child will have a 50% chance of being a DMD carrier. A child who is assigned male at birth will have a 50% chance of having DMD.
Preimplantation genetic testing
People who want to avoid passing on a DMD mutation may choose to undergo preimplantation genetic testing (PGT), which is a procedure doctors use alongside in vitro fertilization (IVF).
IVF involves fertilizing eggs with sperm outside of someone's body in a laboratory. Typically, IVF creates multiple embryos. Doctors can then use PGT to screen the DNA of those embryos for a DMD mutation before implantation in the uterus. Only embryos that test negative through PGT would be candidates for the final stages of IVF.
PGT isn't infallible, though. According to a 2023 literature review, there may be unknown or small duplications or deletions PGT can't detect in certain genetic conditions. It's also not a guarantee that IVF will lead to a pregnancy.
Adoption
People who don't want to pass on a DMD mutation might also consider adopting a child, which can be a highly rewarding experience. There are currently more than 100,000 children waiting for adoption in the United States.
Egg or sperm donation
Another option people may consider along with IVF is using a donor sperm or egg from someone who is not a carrier or affected by DMD.
Duchenne muscular dystrophy (DMD) is a genetic condition that primarily affects people assigned male at birth.
People typically inherit DMD. It's an X-linked recessive condition, which means DMD gene mutations occur on the X sex chromosome.
Due to sex inheritance patterns, only people with two X chromosomes — who are typically assigned female at birth — can be carriers of DMD. People assigned male at birth with a DMD mutation on their X chromosome will develop DMD.
Epicrispr Banks $68M To Test Epigenetic Editing On Rare Muscle Disease
Dive Brief:FSHD is a rare neuromuscular disorder estimated to affect about 870,000 people worldwide. The disease is characterized by progressive muscle weakness that begins in the face, back and upper arms and can leave people in wheelchairs or with debilitating pain and fatigue.
Though there are no available medications for FSHD, drugmakers in recent years have zeroed in on a gene called DUX4. In FSHD, a genetic error causes DUX4 to be overexpressed, eventually resulting in muscle degeneration and atrophy. Biotech companies have been working on various ways, from small molecule drugs to gene therapies, to stop that from happening.
One high-profile effort, an oral drug developed by Fulcrum Therapeutics and Sanofi, failed in Phase 3 testing last year. But other companies, including Avidity Biosciences, Novartis, Arrowhead Pharmaceuticals and Dyne Therapeutics have drugs in development as well. There are currently more than a dozen active DUX4-targeting drug programs, according to the nonprofit FSHD Society.
Epicrispr says its approach is unique among that group. The company is using CRISPR tools to turn genes on or off instead of altering DNA directly. In FSHD, it's harnessing CRISPR to bind a precise region of the DUX4 gene and make a chemical modification. The hope is doing so might stop expression of the encoded protein, without the health risks associated with cutting into DNA.
According to Amber Salzman, the company's CEO, that strategy has shown potential in preclinical tests to impact muscle function and block the DUX4 protein from "seeping out."
"We're going after the absolute root cause" of the disease, she said. "It's a really, really different approach."
Epicrispr CEO Amber Salzman.
Permission granted by Epicrispr Biotechnologies
Salzman has for years worked on genetic disorders as a biotech executive and patient advocate. While at GSK many years ago, her son and two nephews were diagnosed with a rare disease called adrenoleukodystrophy. She connected with prominent gene therapy researcher Jim Wilson, met several other experts in the field and started the nonprofit Stop ALD Foundation.
One of Salzman's nephews died from ALD in 2004. But her son and second nephew received a treatment that was later approved as Skysona. In the meantime, Salzman worked at multiple biotech startups, including eye gene therapy developer Adverum Biotechnologies. In 2021, a recruiter gauged her interest in leading Epicrispr, which was then known as Epic Bio.
By then, the startup had already started working on FSHD — a disease that affected her husband's family, Salzman said. That, and the potential to use epigenetic editing against a wide range of diseases, convinced her to take the job.
"All of a sudden, I found a company that had addressed all the limitations I'd come across in genetic medicine," she said.
Epicrispr raised a $55 million Series A round in 2022. Along with FSHD, it's working on drugs for heterozygous familial hypercholesterolemia, alpha-1 antitrypsin deficiency, a pair of eye diseases and certain undisclosed blood cancers. All of its work is preclinical.
The company was co-founded by Stanford researcher Stanley Qi, who worked closely with gene editing pioneer Jennifer Doudna at UC Berkeley.
A Recent Gene Therapy Death Shines A Light On AAV Safety
This story was originally published on PharmaVoice. To receive daily news and insights, subscribe to our free daily PharmaVoice newsletter.
The death of a 16-year-old boy taking a gene therapy this month dealt a fresh blow to the Duchenne muscular dystrophy community.
The patient died from acute liver failure months after starting Elevidys, the only FDA-approved gene therapy for DMD. Its maker, Sarepta Therapeutics, hasn't ruled out the possibility that the treatment, which uses an adeno-associated virus vector to deliver its therapeutic gene payload, may have contributed to the fatality.
"The Elevidys patient death was due to liver failure, and liver injury is a known side effect of AAV gene therapy. But the investigation is still underway. We should know more in a few months," Sharon Hesterlee, chief research officer at the Muscular Dystrophy Association, said in an email to PharmaVoice.
The teen also had a cytomegalovirus infection, which may have played a role in the outcome, according to Sarepta.
Regardless of what the investigation ultimately reveals, the tragedy raises questions about the safety of gene therapies — especially those made with AAVs.
After AAVs were discovered in 1965, the technology quickly became an appealing alternative to adenovirus vectors, the first type used for gene therapy, because they were less likely to trigger the patient's immune system. But AAVs carry their own set of challenges.
"The primary benefit of AAV vectors is that they are relatively non-immunogenic. This doesn't mean that they cause no immune response, but the response is manageable compared to earlier vectors used like adenovirus, which provokes a strong immune response," Hesterlee said.
AAVs are considered a non-integrating virus, meaning they don't routinely insert their genetic material into the cell's chromosomal DNA and are less likely to lead to cancer. However, this benefit comes with a trade-off: The therapeutic gene isn't copied during cell division, causing it to dilute quickly in body tissues that rapidly divide, such as the skin, Hesterlee said. In other tissues, such as nerves, muscles or ocular tissues, AAVs can produce long-lasting gene expression, she said.
But AAVs are relatively small, which limits the payload they can carry compared with adenovirus vectors. For this reason, Elevidys uses a shortened and less functional portion of the dystrophin gene, micro-dystrophin, to treat DMD. AAVs are also expensive to make, and patients with pre-existing immunity to the different serotypes of the virus could get hit with side effects that rule it out as a therapy option, Hesterlee said.
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While AAV-related immune reactions are less likely, the risk is not zero, Jake Mathon, director of cardiometabolic, infectious and genitourinary diseases at Citeline, said in an email to PharmaVoice. These responses can sometimes lead to liver damage, heart inflammation or the formation of small blood clots that damage organs or tissues. Even so, companies still see value in AAVs.
To date, more than 500 AAV gene therapy drugs are in development and six have been approved, Mathon said. But companies are also exploring viral and non-viral options.
"Lentiviruses and retroviruses are often used for cancer-focused gene therapy or gene therapy in tissues where cells are dividing," Hesterlee said.
Genelux, EG 427 and SillaJen Biotherapeutics are all testing gene therapies using lytic virus, Herpes simplex virus or poxvirus. Ring Therapeutics is exploring anelloviruses.
Currently, there are more than 200 active gene therapy drugs that use these alternative vectors with 24 approvals, Mathon said.
"There is also a lot of interest in non-viral vectors, such as lipid nanoparticles or exosomes — these non-viral vectors may potentially allow repeat dosing and be cheaper to manufacture but the jury is mostly still out as they are all very new," Hesterlee said.
Despite the potential risks of AAVs, they remain a promising delivery system for gene therapies.
"It is likely that [the] industry will continue with AAV development as there has been some success so far," Mathon said. "There may need to be some more stringent warning labels regarding certain risks and mitigations to prevent those risks. But the industry will continue down this road, especially in the short term, as well as exploring other options that may prove to be safer in the long run."
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