Research News

Texas Children’s to offer brand new FDA-approved treatment for Spinal Muscular Atrophy

Texas Children’s Hospital is among the first hospitals in the nation to offer the new FDA-approved treatment for Spinal Muscular Atrophy (SMA) to pediatric patients. Texas Children’s inaugurated this program in February 2017 for established and newly diagnosed SMA patients.

SMA is a rare genetic disease affecting muscle strength and movement. About one in 10,000 babies are born worldwide with SMA, and it is among the leading genetic causes of death in infants. This inherited condition is caused by a mutation in a gene (SMN1) that produces Survival Motor Neuron (SMN) protein, which is essential to the normal function and survival of motor neurons. Motor neurons are nerves that control skeletal muscles. If motor neurons cannot function properly or are dead, it can lead to progressive debilitating weakness of all muscles in the body, including those important for breathing.

Humans have two closely related versions of the SMN gene, SMN1 and SMN2. Normally, SMN1 produces a fully functional SMN protein 100% of the time as the motor nerve cell “reads” the gene code and splices the amino acids together to make the protein.  However, a “clumsy reading” defect in the SMN2 gene leaves out a critical amino acid (a splicing defect), which means this gene produces normal SMN protein only 10% of the time. Thus, motor nerve cells totally depend on SMN1 since it is the “workhorse” that produces normal SMN protein.

Individuals affected by SMA have a defective SMN1 gene, resulting in a near complete deficiency of SMN protein, except for the small amount produced by SMN2, which is not enough for muscles to work in the usual manner.

Usually, humans can have anywhere from two to eight copies of the SMN2 gene, which incrementally increases the amount of SMN protein produced. More copies of SMN2 help to delay the onset of SMA symptoms.  Children with only two copies are weak from birth or within the first six months.  Those with two or more copies develop symptoms of weakness later in infancy or childhood.

Basic and clinical research at the University of Massachusetts Medical School, Cold Spring Harbor laboratory, Ionis Pharmaceuticals and Biogen led to a DNA-based antisense oligonucleotide therapy that corrects the “clumsy reading” (splicing defect) of the SMN2 gene such that it produces the SMN protein nearly 100% of the time that the motor nerve cell uses that code. Anti-sensense oligonucleotides are small pieces of synthetic genetic material that can fix errors during production of proteins from their starting material, DNA. This drug is being marketed as Spinraza (nusinersen).

It is administered intrathecally, i.e. by injection into the spinal canal through a lumbar puncture procedure, so that the drug reaches the cerebrospinal fluid directly and can then have access to the motor nerve cells in the spinal cord.  The drug cannot efficiently reach the spinal fluid or spinal cord through the bloodstream. Initially, patients receive four doses in the first two months followed by booster doses every four months for rest of their life.

“The good news is that in the clinical trials, SMA type 1 patients, who are among the most severely affected from birth, showed significant benefits in motor skills and breathing over placebo control patients. These infants, who would otherwise not be expected to even lift their heads, were rolling over, sitting up, and some even standing on their own.  In addition, many of the treated infants did not need breathing support, which is truly amazing for patients with this disease.  Siblings of SMA patients who were diagnosed and treated before muscle weakness set in, did not develop disease symptoms at all!  Depending on the severity of the patient’s symptoms, it can take about six months to a year to see improvements in muscle strength and other outcome measures”, said Dr. Timothy Lotze, neurologist and clinical medical director of the Muscular Dystrophy Association Care Center at Texas Children’s Hospital, where such patients are treated.

It is important to note that as with any drug, there could be some potential side effects associated with Sprinraza therapy. In the clinical trials, these were generally mild and principally included headaches after lumbar puncture. Moreover, since this is a medically fragile population consisting mainly of young children, some of who may have associated breathing difficulties, scoliosis and osteoporosis, there must be careful consideration as to how and where the lumbar puncture will be performed, as some of them may require assistance from interventional radiology.

Another potential drawback for this therapy is the exorbitant price tag of this orphan drug of $125,000 per dose. Insurance companies have now begun to negotiate prices with the drugmakers and it is hoped that consumers may not have not bear the full burden of this high cost in the near future. In addition, Biogen has established a program, SMA 360, to help patients facing “non-medical barriers” to treatment, such as financial problems or trouble with coverage.

“Regardless of these issues, until Sprinraza was developed, we could not offer SMA patients any treatment options, other than supportive care. For the first time, this drug offers the possibility of stopping, recovering and perhaps, even preventing SMA symptoms.  It is truly a “game-changer” for these patients,” concluded Dr. Lotze.

Rajalaxmi Natarajan, Ph.D.
April 11, 2017