Nationwide Children's SMA Gene Therapy Trial

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"1.  Replacement or Correction of the SMN1 Gene

SMA is caused by a mutation in the SMN1 gene. Researchers believe we may be able to treat SMA by replacing or correcting this faulty gene.  

Gene therapy, also called gene transfer, is the focus of current research on the faulty SMN1gene. In addition to replacing or correcting the SMN1 gene, gene transfer therapies could also be used to help protect motor neurons, the main cells affected by SMA. 

How Gene Transfer Works

Gene transfer uses a piece of DNA from a particular gene, such as SMN1 for SMA.  It isn’t possible to insert the gene directly into a cell, so scientists use a carrier, called a vector, to deliver the gene to the cell. A vector is a virus that “infects” the cell with the new DNA. The virus is modified so that it doesn’t make the person sick.

Challenges of Gene Transfer 

Gene transfer for SMA presents a unique challenge, because the cells we need to reach are in the spinal cord, so the vector has to cross the blood-brain barrier. The blood-brain barrier is a semi-permeable covering that protects the brain from foreign substances and maintains a constant brain environment. Cure SMA is working with top scientists to address this challenge, ensuring gene transfer techniques for SMA can cross this barrier. 

Cure SMA Funding for Gene Transfer

In 2010, Cure SMA made a $100,000 drug discovery grant to Dr. Brian Kaspar for SMA gene therapy development. Dr. Kaspar’s project tested Adeno-associated virus type 9 (AAV9), to see if that virus could cross the blood-brain barrier at different ages, and to investigate how quickly we need to target motor neurons in children with SMA in order for the treatment to be effective.

Ongoing Research and Testing

In 2012, we awarded Dr. Kaspar a second grant of $750,000 to support his work on gene therapy delivered specifically to the central nervous system (CNS-delivered gene therapy). With this additional grant, Dr. Kaspar was able to test for an optimum dosage in both mice and non-human primates. 

Taking Gene Therapy Toward Clinical Trials

In 2013, Dr. Kaspar received a nearly $4 million government grant from the National Institute of Neurological Disorders and Stroke (NINDS), using the early data generated with our funding. 

The grant supports additional work needed to move CNS-delivered gene therapy toward clinical trials through submission of an Investigational New Drug (IND) application to the FDA. This project represents an important collaboration between researcher, government, and Cure SMA.

Phase 1 Clinical Trial for Systemic Gene Therapy in Infants

Following the submission of the IND application in late 2013, the FDA gave approval to begin a Phase I clinical trial of a systemic AAV9-delivered human SMN gene. The clinical trial began in April 2014 and is enrolling nine infants age 0 to 9 months. 

Though the current AAV9-delivered clinical trial is enrolling infants, the Cure SMA-funded CNS-delivered gene therapy could allow older and larger people with SMA to be treated by gene therapy. Cure SMA’s ongoing investment in this project may eventually make this treatment available to a wider population.

2.  Modulation of the SMN2 "Back-Up Gene" 

All patients with SMA have at least one copy of survival motor neuron gene 2 (SMN2), often referred to as the SMA back-up gene. Many individuals have multiple copies of this gene, and in general, it seems that individuals with more copies have a less severe form of SMA.

SMN2 only makes a small amount of functional SMN protein. Most of the SMN protein made by SMN2 is missing an important piece, called exon 7. A number of strategies that targetSMN2 are being explored. These treatment approaches may:

Correct SMN2 mRNA splicing, meaning SMN2 could produce a complete protein.
Prompt SMN2 to make more protein. 
Make the protein produced by SMN2 last longer.

Antisense Oligonucleotides

Antisense drugs are small snippets of synthetic genetic material that bind to ribonucleic acid (RNA), so they can be used to fix the splicing of genes like SMN2. Antisense oligonucleotides (ASOs) can target the sequences in SMN2 pre-mRNA that are needed to include the missing exon 7.

Cure SMA Funding for ASOs

From 2003 to 2006, Cure SMA provided the seed funding needed to begin investigation into this therapeutic approach.  

Several Cure SMA grants totaling over $500,000 were given to Dr. Ravi Singh at U Massachusetts, to help develop the intellectual property needed to investigate ASOs for SMA. The intellectual property generated with our funding was then licensed to Isis Pharmaceuticals for an SMA drug called ISIS-SMNRx.  

Since then, we have continued to provide funding for this approach, including:

A $150,000 grant in 2013 to Dr. Christian Lorson and Dr. Arthur Burghes, to assess new, second-generation ASOs that target different parts of SMN2 splicing.  
A $150,000 grant, also in 2013, to Dr. Yimin Hua and Dr. Adrian Krainer at Cold Spring Harbor Laboratory to look at the influence of backbone chemistry on ASOs for SMA.  

Ongoing Testing of ASOs for SMA

Isis is currently conducting Phase III clinical trials for ISIS-SMNRx. Testing will be conducted for both children and infants. 

For further information on any of the following studies, and for contact information for the study sites, please visit and search for ISIS-SMNRx. You may also contact Kristina Bowyer at Isis directly.  

Small Molecules

Small molecules are chemicals that treat or cure a disease. In SMA, small molecules might be used to correct SMN2 mRNA splicing or cause SMN2 to make more protein, or make that protein last longer. 

A multi-step process is used to convert small molecules into drugs:

Identifying chemicals that might work for SMA. Through a process called high throughput screening, researchers often screen hundreds of thousands of chemicals just to find one candidate
Turning chemical compounds into drugs. Using medicinal chemistry, scientists modify the chemical many times over, trying to improve it each time in order to make it into a useable drug.
Evaluating the efficacy and safety through animal studies. Scientists first test the optimized candidate drugs in animals to make sure it is ready for human testing.
Submitting the IND to the FDA. The data is submitted in the form of an Investigational New Drug (IND) Application. Within 30 days, the FDA will either approve or place a hold on human clinical trials. 

Ongoing Small Molecule Programs for SMA

A number of companies and academic laboratories have small molecule programs that may address the SMN2 gene.  They include: 

Pfizer (Phase I trials)
Roche / PTC Therapeutics (Phase I trials)
Novartis (preclinical)
Paratek (preclinical)
CALIBR (preclinical)
Rubin lab at Harvard University (preclinical)
Androphy lab at Indiana University (preclinical)

Cure SMA Funding for Small Molecules

Cure SMA has invested $19 million in SMA drug development since 2000. This includes investment in four small molecule drug programs, as well as alternative approaches. 

Quinazoline Program

Cure SMA began funding this program in 2000. In 2009, the FDA granted Orphan Drug Designation to this drug, meaning it is eligible for special incentives that encourage drugs development for rare conditions. Also in 2009, Cure SMA licensed these compounds to Repligen Corporation for clinical development.  In 2013, Repligen licensed the compounds to Pfizer, the world's largest pharmaceutical company.  

Tetracycline Program  

In 2006, Cure SMA began funding this program at Paratek Pharmaceuticals. Cure SMA’s seed funding allowed Paratek to gather preliminary data, which was used for an NIH grant application. Paratek was then awarded a multi-million dollar cooperative agreement from NINDS to continue their research.

Calibr Program  

Cure SMA began funding this program in 2011.  Led by renowned chemist Peter G. Schultz, this ongoing work focuses on optimizing chemical properties of small molecule enhancers of SMN protein.

Harvard Program  

Cure SMA funded this program in 2013 and 2014.  It focuses on small molecule drug screening in motor neurons, with the hope of finding new potential therapies for SMA. The project is led by Dr. Lee Rubin.

3.  Neuroprotection

Motor neurons are one of the primary cell types affected in SMA. Motor neurons are nerve cells that control muscle movement.  In SMA, the motor neurons cannot properly function and eventually die, leading to debilitating and often fatal muscle weakness.   

The goal of neuroprotection is to protect motor neurons by restoring their function and/or preventing their death. Unlike approaches that treat the SMN1 or SMN2 gene, this approach does not address the underlying genetics. However, neuroprotection could be readily used in combination with therapies that fix the SMN1 or SMN2 gene. 

Currently, two main neuroprotective strategies are being studied for SMA:

Neuroprotective small molecules that help cells stay alive.
Stem cells transplants that provide growth factors to motor neurons.  


Olesoxime (TRO19622) is a neuroprotective small molecule being pursued by Trophos, a French company. 

At the 2014 American Academy of Neurology Meeting, Trophos presented data on a clinical trial for olesoxime for SMA. This trial tested a group of individuals who have SMA type II or III. Individuals who received olesoxime maintained their motor function better than individuals who received a placebo. In addition, health complications associated with SMA occurred less frequently with olesoxime than with the placebo.

Trophos is planning a New Drug Application to the FDA in the United States and the EMA in Europe. 


MotorGraft is a product being developed by Neostem (formerly California Stem Cell). Cells derived from human embryonic stem cells (hESCS) are transplanted into the spinal cord to provide growth factors to the remaining motor neurons, helping the individual to function better and live longer.

In 2010, an Investigational New Drug (IND) application was submitted to the FDA to begin clinical trials in infants with SMA.  In 2011, the FDA placed the MotorGraft program on clinical hold, in order to obtain additional supporting data. The program remains on hold today.

4.  Muscle Protection

Low levels of the SMN protein disrupt the proper function of the nerve cells that control our muscles, called motor neurons.  The loss of nerve stimulation causes the skeletal muscles to atrophy in SMA. 

As the name would suggest, the goal of muscle protection is to protect these muscles from atrophy, increase muscle mass, and perhaps even restore some muscle function. Similar to neuroprotection, this strategy does not address the underlying genetics. But it may slow or stop the progression of SMA, and it can be used in combination with approaches that fix theSMN1 or SMN2 genes.

These approaches, which may be more appropriate for milder types of SMA, may include:

Small molecules that enhance the muscle’s ability to contract. 
Regulators of muscle mass that may improve muscle strength.

Cure SMA Funding for Muscle Protection

In 2013, Cure SMA made a drug discovery grant to Cytokinetics, to help fund the study of Tirasemtiv for SMA.  Tirasemtiv has been studied in clinical trials for individuals with ALS. ALS and SMA are similar in that both affect the motor neurons. 

Cure SMA’s funding will allow Cytokinetics to expand their testing to see if this drug could also be effective for individuals with SMA. Cytokinetics is examining the effects of Tirasemtiv on leg and respiratory muscle function, and whether Tirasemtiv may reduce fatigue and improve muscle strength during exercise.

Regulators of Muscle Growth for SMA

The use of regulators of muscle growth for SMA is still in the very early stages of study, and the results have been mixed in SMA animal models. It also appears from this early data that this approach may be more appropriate for milder types of SMA.

CURE SMA's Therapeutic Approaches

"One of the strengths of Cure SMA’s drug discovery program is how we attack SMA from multiple angles. This also gives us great reason for hope. We know that if one approach fails, we have several others we can pursue.

Researchers have identified four different therapeutic approaches that show promise in treating SMA:  

1. Replacement or correction of the faulty SMN1 gene 
2. Modulation of the low functioning SMN2 "back-up gene" 
3. Neuroprotection of the motor neurons affected by loss of SMN protein
4. Muscle protection to prevent or restore the loss of muscle function in SMA"  (

Working towards treatment and a CURE !

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