Antisense Oligonucleotides for Treating Neuromuscular Disease

Antisense oligonucleotides block flawed genetic instructions
Antisense oligonucleotides — also called antisense, oligos, or simply AONs — are pieces of genetic code that keep other genetic code from being processed. developed to pair up with a particular sequence of DNA or RNA, AONs can change, block or destroy specific genetic guidelines in a selection of ways.

In facioscapulohumeral muscular dystrophy (FSHD), the apparently toxic DUX4 protein guidelines potentially may be blocked by AONs. In type one myotonic dystrophy (MMD1 or DM1), genetic guidelines for the DMPK protein might be blocked or destroyed by AONs. Laboratory experiments in these diseases have had promising earlier results.

In type two myotonic dystrophy (MMD2 or DM2), AONs potentially could interfere using the genetic guidelines for the ZNF9 protein. These experiments are not yet under way.

In the SOD1-related form of familial ALS (amyotrophic lateral sclerosis), AONs could block the genetic guidelines for toxic SOD1 protein. A clinical trial to test this method is under way in participants with SOD1-associated familial ALS.

In Duchenne muscular dystrophy (DMD), AONs may be used to mask certain segments of genetic guidelines for the dystrophin gene, so that a functional dystrophin protein may be made. This strategy — known as exon skipping because it causes the cellular to skip over certain regions (exons) within the genetic guidelines for the dystrophin gene — presently is being examined in clinical trials.

In spinal muscular atrophy (SMA), the goal is to use AONs to alter the way the cellular reads genetic guidelines for the SMN protein that’s lacking in this disease, so that a functional SMN protein may be produced.

Experiments are under way to induce inclusion of a part within the SMN gene called exon 7. in this case, AONs would induce exon inclusion rather than exon skipping.

Stem cells can display ‘disease in a dish’
Stem cells are cells in the quite earlier stages of development. They could possibly be destined to turn right into a particular cellular type (such as muscle or nerve cells) or they could possibly still retain pluripotency — the capability to develop into any of a number of different cellular types.

Scientists now are functioning with induced pluripotent stem cells or iPSCs, that are mature cells — sometimes taken directly from the patients themselves — that happen to be reprogrammed right into a stemlike state. From there they may be coaxed to become whichever type of cellular is needed.

Patient-derived iPSCs are being used in FSHD to study how the condition develops and to test potential therapies in a “disease in a dish.”

In ALS, disease-affected stem cells serve as models for studying the condition process and screening potential therapeutic strategies.

They also are in development as cell-transplantation therapies. In an ongoing ALS clinical trial, neural precursor cells derived from a fetal spinal cord are being injected into participants’ spinal cords.

In a different ALS clinical trial, transplantation in to the spinal cord of mesenchymal stem cells, derived from bone marrow, has been found to become equally feasible and safe.

In DMD, different kinds of muscle stem cells could possibly replace or fix degenerating muscle fibers. A clinical trial is under way in Italy to test the security and possible benefits of a type of stem cellular known as the mesoangioblast, which is associated with blood vessels but which can develop into muscle tissue.

Small-molecule drugs effectively target tissues and pathways
Synthesized small-molecule drugs are considerably scaled-down than proteins and many occasions scaled-down than cells, generating them frequently easier to provide to specific tissues and less very likely to elicit an undesirable immune response.

A little molecule belonging to a chemical class of compounds called histone deacetylase (HDAC) inhibitors is being developed like a potential remedy for Friedreich’s ataxia (FA).

Also being studied in FA are little molecules known as antioxidants, which can counteract a type of cellular harm known as oxidative stress.

In SMA, a little molecule under development is developed to alter the way cells interpret the genetic guidelines for SMN, coaxing manufacturing with this required protein.

In DMD and also the associated Becker muscular dystrophy (BMD), clinical trials are under way of a little molecule known as sildenafil (brand title Viagra) and also a similar little molecule, tadalafil (brand title Cialis). These drugs appear to boost blood flow to exercising muscle and also have cardiac consequences that could possibly be beneficial in DMD and BMD.

Another emerging use of little molecules in DMD, and possibly in BMD, would be to combat inflammation.

Inflammation-reducing corticosteroids like prednisone and deflazacort are widely used in DMD, but they have undesirable aspect effects, such as fat gain and bone loss, if given for long periods at fairly higher doses.

Efforts are under way to develop anti-inflammatories without the aspect consequences of corticosteroids. A little molecule compound known as VBP-15 seems promising, and is also very likely to become carried forward into clinical trials.

In ALS, little molecules are being used to target the cell-death pathway in motor neurons. A little molecule called necrostatin one seems to become a potent inhibitor within the BNIP3 cellular death pathway.

A similar strategy is being investigated for SMA, in which a degenerative pathway known as JNK is being specific by a little molecule developed to inhibit JNK signaling.

In centronuclear myopathies (CNMs), including myotubular myopathy (MTM), evidence factors to a defect at the neuromuscular junction, the place where nerve and muscle fibers meet.

Some with CNM/MTM have responded to a small-molecule drug called pyridostigmine (brand title Mestinon), which has been used for many years to treat neuromuscular transmission defects such as those people that occur in myasthenia gravis (MG) and other types of myasthenia.

Pyridostigmine seems to modestly boost function and could possibly improve quality of life for some with these conditions.

Protein therapies are difficult to develop, with some notable exceptions
Proteins hold out the majority of cellular features in the human body. many types of neuromuscular condition are caused by missing, deficient or toxic proteins.

But development of protein-based therapeutic agents frequently poses additional problems than development of other kinds of therapies. this is due to many factors.

Protein molecules’ big size and other properties will make it difficult to obtain them into cells. Delivering the molecules to the right cells is another challenge.

Once inside cells, proteins could possibly be modified, recycled, or degraded and destroyed by cellular “housekeeping” machinery.

Unwanted immune responses not only can neutralize protein treatment but can induce harmful reactions in patients.

When created in big quantities (for mass marketing), inherent characteristics of protein molecules change, such as stability or the threat of misfolding and/or clumping.

Nonetheless, there happen to be remarkable success stories in this field.

A shining instance is the approval through the U.S. foodstuff and drug administration (and regulatory agencies in other countries) of Myozyme and Lumizyme to treat Pompe condition (acid maltase deficiency or AMD). The drugs replace the missing or deficient acid maltase protein.

In DMD, the protein biglycan seems to attract the beneficial protein utrophin to the muscle-fiber membrane in animal experiments. Utrophin can partially compensate for the dystrophin protein missing in this disease.

Administering the protein laminin 111 has shown benefit in animal models of congenital muscular dystrophy (CMD) that is caused by the loss within the laminin alpha two protein.

A protein called netrin one seems to defend nerve fibers in laboratory experiments and has potential in Charcot-Marie-Tooth condition (CMT) and Dejerine-Sottas disease.

Gene treatment could yield long-term treatments, when problems are addressed
Gene therapy, or gene transfer, refers to the delivery of genes as therapeutic agents. since genes hold the guidelines for protein synthesis, they are able to lead to manufacturing of proteins which can be directly or indirectly therapeutic in neuromuscular diseases.

Because transferred genes potentially can continue to produce protein for some time, gene treatment could possibly offer a additional permanent fix than other therapies.

But gene treatment faces many specialized challenges, too like a higher bar arranged by regulatory agencies like the FDA.

The crucial problems are:

delivering the genes to the specific tissue even though keeping away from off-target tissues; and
avoiding undesirable immune response to the proteins created from the new genes, or to the delivery vehicles in which the brand new genes are delivered.
Gene treatment for DMD has been in development for many years. A recent clinical trial involving injection of a miniaturized dystrophin gene uncovered unexpected kinds of immune responses which can be not yet completely understood and are being explored.

Although the treatment was found to become safe, at least at the lower doses used, the immune responses appear to possess interfered with prolonged manufacturing within the dystrophin protein. Immunosuppressant drug remedy could possibly be necessary in conjunction with dystrophin gene transfer in humans.

Another type of gene treatment being considered in DMD involves transferring genes for the protein claudin 5 to treat cardiac elements within the disease. This method has shown amazing promise in treating heart-muscle harm in a computer mouse model within the disease.

Blocking the myostatin protein via a protein called follistatin is a strategy that has potential for treating DMD and very likely many other neuromuscular diseases. Mice with a DMD-like condition that received genes for the follistatin protein showed an general boost in body mass and fat of man or women muscles. Monkeys that received follistatin gene transfer had stronger, bigger muscles.

In FSHD, genes for antisense oligonucleotides are in development that block toxic proteins in a computer mouse model within the disease. This strategy could provide long-term manufacturing of protein-blocking agents.

Also in development is a gene treatment strategy that involves transfer within the dysferlin gene, which is mutated in the type 2B form of limb-girdle muscular dystrophy (LGMD2B) and in distal muscular dystrophy (Miyoshi myopathy). results in dysferlin-deficient mice are encouraging.

Delivery of genes to the central nervous method has been complicated through the blood-brain and blood-spinal cord barriers. a new delivery vehicle, centered for the shell of a type 9 adeno-associated virus (AAV9), has overcome this barrier in laboratory models of SMA.

Mice with an SMA-like condition have shown remarkable benefit from the delivery of SMN genes in AAV9 shells and also the strategy is being considered for human clinical trials. A caveat is that SMN could possibly need to be given quite earlier in life for maximum benefit.

Multiple strategies boost the chances of success
Although they hold promise, the 5 strategies described here still should undergo additional refinement and rigorous testing before they are able to receive FDA approval for use in humans.

But, the additional potential therapies under development, the much better the odds 1 or additional will work.

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