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Cover page of the Journal of Health Sciences

 Table of Contents  
Year : 2019  |  Volume : 12  |  Issue : 3  |  Page : 189-195

Gene therapy for childhood neuromuscular and neurodegenerative disorders: An update

Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication15-Oct-2019

Correspondence Address:
Dr. Prateek Kumar Panda
Room No. 224, RPC - 1 Hostel, All India Institute of Medical Sciences, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kleuhsj.kleuhsj_81_19

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The central nervous system is a rather complex site for gene therapy as it contains neurons, astrocytes, and oligodendrocytes, and they have discrete and intricate interconnections between them, establishing a delicate balance. However, with significant advances in scientific technology and development of new viral vectors, now, gene therapy has a greater promise for pediatric neurological disorders, especially for certain neurodegenerative diseases, which still remains to be invincible by other pharmacological modalities. Adeno-associated virus (AAV) vector is the predominant vector used for gene therapy currently. Gene editing therapy using antisense oligonucleotides has been successfully implemented in neuromuscular diseases such as dystrophinopathy and spinal muscular atrophy (SMA). Recently, an AAV-mediated gene therapy is approved by the Food and Drug Administration for SMA, and it is considered to be the most expensive drug in the world. Gene therapy for dystrophinopathy has also been safely tried in two clinical studies, although its efficacy is yet to be demonstrated. In Xlinked adrenoleukodystrophy, late infantile metachromatic leukodystrophy, late infantile neuronal ceroid lipofuscinosis and Canavan disease results of human trials are very much promising. Ongoing clinical trials in several lysosomal storage disorders such as mucopolysaccharidosis type III, Fabry disease, and Pompeii disease are currently active. In mouse models, several other neurodevelopmental disorders have also been tested successfully for gene therapy.

Keywords: Childhood, gene therapy, neurodegenerative, neuromuscular

How to cite this article:
Panda PK. Gene therapy for childhood neuromuscular and neurodegenerative disorders: An update. Indian J Health Sci Biomed Res 2019;12:189-95

How to cite this URL:
Panda PK. Gene therapy for childhood neuromuscular and neurodegenerative disorders: An update. Indian J Health Sci Biomed Res [serial online] 2019 [cited 2020 Jul 12];12:189-95. Available from: http://www.ijournalhs.org/text.asp?2019/12/3/189/269207

  Introduction Top

The central nervous system (CNS) is a rather complex site for gene therapy as it contains neurons, astrocytes, and oligodendrocytes, and they have discrete and intricate interconnections between them, establishing a delicate balance. However, with significant advances in scientific technology and development of new viral vectors, now, gene therapy has a greater promise for pediatric neurological disorders, especially for certain neurodegenerative diseases, which still remains to be invincible by other pharmacological modalities.[1] Most stupendous success in the field of gene therapy is for children with dystrophinopathy and spinal muscular atrophy (SMA). For various leukodystrophies such as adrenoleukodystrophy (ALD) and lysosomal storage diseases also, gene therapy has been found to be successful. This review briefly describes the various successful gene therapy options in human and animal models of childhood neurological disorders initially. However, initially, the review provides a brief overview of vectors and the process of gene therapy.[1]

  History Top

The first successful gene therapy in children was done in a girl suffering from severe combined immunodeficiency with adenosine deaminase (ADA) deficiency on September 14, 1990. However, the child continued to receive recombinant enzyme even after gene therapy, raising doubts on the success of gene therapy. Later on, however, a French group demonstrated the long-term success of gene therapy in children with X-linked immunodeficiency in the 1990s.[2] Two of these patients, unfortunately, developed leukemia-like state, thereby confirming the risk of malignancy due to gene therapy. To add further, Jesse Gelsinger, a patient who participated in a clinical trial for ornithine transcarbamoylase deficiency, died on the 4th day of gene therapy, probably due to severe immune reaction to the adenovirus used as a vector for carrying the gene. The child had acute lung injury, hepatic failure, and coagulopathy following gene therapy and expired subsequently.[2] These serious adverse reactions raised a lot of ethical concern. However, in the last two decades, a lot of progress had been achieved in the development of newer safe vectors and immunosuppression.[2]

  Mechanism of Action of Gene Therapy Top

The most common mechanism of gene therapy utilized in clinical practice is the insertion of normal gene into a nonspecific location within the genome to replace the nonfunctional gene.[2] Gene editing through antisense oligonucleotides (ASOs) also has significant clinical relevance for neuromuscular disorders such as dystrophinopathy and SMA. Only in few cases, an abnormal gene is swapped for a normal gene by homologous recombination or is repaired through selective reverse mutation.[3]

  Type Of Gene Therapy Top

Gene therapy can be a somatic cell gene therapy and germline gene therapy. In somatic cell gene therapy, the gene is transferred into the bone marrow cells, peripheral blood, or even directly intracerebrally. On the other hand, in germline gene therapy, the gene is transferred into the sperms or ovum, thereby making them heritable to the next generation.[3] Due to safety and ethical concerns, all the current researches are limited to somatic cell gene therapy. Gene therapy is divided into in vivo and ex vivo types depending on whether genetic correction occurs inside or outside the body.[3]

In vivo gene therapy

In this, the vector first enters into the target cell, the therapeutic gene enters into the target cell's nucleus, and then the functional protein is expressed, thereby returning the cell to normal state. The therapeutic gene carried by the vector can remain free in the nucleus as extrachromosomal material or it can be integrated into the genome.[4]

Ex vivo gene therapy

The viral vector is altered so that it cannot reproduce; the targeted genetic material is inserted into its genome. Then, the viral vector is mixed with the cells collected from the patient and reinfused after transduction. Then, these cells divide in vivo and produce the functional enzyme/protein.[4]

  Method of Gene Therapy Top

Biological methods using viral vectors, plasmids, cosmids, and naked DNA are various methods commonly used in gene therapy in research settings.[5] Out of these, viral vectors are most commonly used in clinical practice, and the characteristics of an ideal viral vector are it should be highly specific for the targeted cell, capable of efficiently delivering into target cell, other essential characteristics are feasibility to produce the purified version in large quantities at high concentration, minimal allergic reaction or inflammation, safe for the patient and the environment, and longterm expression inside the recipient, preferably life long.[5]

  Viral Vectors Top


By using reverse transcriptase, it produces double-stranded viral genome which integrates into human genome by integrase. Integrase inserts the gene anywhere because it has no specific site and may cause insertional mutagenesis. Zinc finger nuclease can be used for targeting the insertion to specific site. Vectors derived from HIV and other lentiviruses are being evaluated for safety concerns. The packaging capacity is around 8 kb.[5]


They have double-stranded DNA genome and can cause respiratory, intestinal, and eye infections in humans. The inserted DNA is not incorporated into the genome and is left free in the nucleus. It can infect slowly dividing cells. It can also spread into the surrounding cells. Immunogenic response is more severe with adenovirus as compared to adeno-associated virus (AAV). The packaging capacity is around 7.5 kb.[6]

Adeno-associated virus

It is from parvovirus family with small, single-stranded DNA that inserts genetic material at a specific point on chromosome 19 with near 100% certainty. It causes no known human disease and does not trigger patient immune response. The gene is always “on,” so the protein is constitutionally expressed, possibly even in instances when it is not needed. The packaging capacity is around 4.5 kb (small).[7]

Herpes simplex virus

It is a double-stranded DNA virus that infects the neurons. It has a large genome compared to other viruses, which enables scientists to insert more than one therapeutic gene into a single virus, paving the way for treatment of disorders caused by more than one gene defect. Herpes simplex virus (HSV) makes an ideal vector as it can infect a wide range of tissues including muscle, liver, pancreas, and nerve and lung cells.[8] The wild type of HSV-1 virus can infect neurons which are not rejected by the immune system. Antibodies to HSV-1 are common in humans; however, complications due to herpes infections are comparatively rare. Recent advances in AAV have produced recombinant DNAs, which get inserted at the end of chromosomes producing episomes, thereby reducing the probability of mutation along with long-standing gene expression.[8]

  Newly Discovered Novel Methods of Gene Therapy Top

RNA interference or gene silencing is a recently recognized mechanism, which is being explored now for a large number of diseases. siRNAs are small RNA molecules with homology to specific mRNA molecules and after binding to the mRNA, they will suppress the translation of the defective protein and degrade RNA of a particular sequence.[9] As a result of which, abnormal protein will not be produced, and the cell will return to its normal function. A single ASO can cause significant reduction in the level of mutant huntingtin, ataxin 1 and 3, and atrophin-1, thereby being effective in several trinucleotide repeat mutation with polyQ (polyglutamine disorders). Based on these principles, several molecules have been developed, and many of them are about to complete preclinical stage.[10]

First of all, intracellular dsRNA is recognized by an RNase III (designated as “Dicer” in Drosophila) and cleaved into siRNAs of 21–23 nucleotides. These siRNAs are then integrated in a complex (designated as “RISC,” RNA-induced silencing complex). Each siRNA in RISC is specific and targets certain sequences of mRNAs, which is homologous to the integral siRNA followed by complete degradation of targeted mRNA.[11] In fact, the target mRNA is cleaved at the center of the sequence complementary to the siRNA. As a result, when AAVs carrying the siRNA gains enter into neuronal cell, rapid degradation of the target mRNA and decreased protein expression were observed. However, only a few leukodystrophies follow autosomal dominant inheritance. siRNA-associated gene therapy has been done with some success in SCA type, 1, 3, and 6, which can also be seen in pediatric population.[11]

  Problems Associated With Gene Therapy in Neurological Disorders Top

It is difficult for vectors to cross the blood–brain barrier and infect neurons. However, hematopoietic stem cell can enter into the CNS and get converted into microglia cells.[12] They can provide enzymes to the nearby cells. Short-term expression of the gene therapy; development of immunity against viral vector, making the vector inefficient with repeated use; and large size of gene (beyond packaging size of vector) are other difficulties faced by researchers while implementing gene therapy for neurological disorder.[12] Some of the genes if overexpressed can cause neuronal damage as with MECP2 gene for Rett syndrome.[12]

Intracerebral insertion, despite better efficacy, can have serious side effects. Intrathecal or intraventricular administration does not necessarily produce the same effect as intracerebral administration.[13] The number of sites, dose of vector, and the method of insertion are not standardized. The location of a gene in the genome is of importance for the degree of expression of the gene and for the regulation of the gene (the so-called “position effect”), and thus the gene regulatory aspects are always uncertain after gene therapy.[13]

  Human Studies on Gene Therapy in Pediatric Neurological Diseases Top

Apart from dystrophinopathy and SMA, mouse models with gene therapy have been successfully tried in preclinical studies in leukodystrophies, lysosomal storage disease, and neuronal ceroid lipofuscinosis (NCL).[2] For few diseases, human trials have been successfully completed, and the results are described in [Table 1]. For some other diseases, Phase I/II clinical trials have been started, and the result is yet to be published.[6]
Table 1: Clinical studies describing successful gene therapy in various neurological disorders of childhood

Click here to view

  Dystrophinopathy Top

The most common form of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by a mutation in the DMD gene, which codes for a protein called dystrophin. Dystrophin is part of a protein complex that binds sarcoglycan–dystroglycan complex with the cell membrane. When the cells do not have functional dystrophin due to the gene mutation, the cytoskeleton of myocyte weakens, ultimately leading to myocyte necrosis. Currently, ASOs such as Eteplirsen and Ataluren have been approved for DMD with exon 45–51 deletion and nonsense mutation, respectively.[13] These ASOs alter the reading frame of coding strand and mRNA, thereby producing a functional dystrophin protein. Supplying a gene that codes for a functional form of dystrophin will be an effective treatment for DMD, but it is extremely challenging because of the large size of DMD gene, which will not fit into the commonly used viral vectors. Gene editing with these ASOs has opened a promising new avenue of hope for patients with DMD. While Exondys (Eteplirsen) is a targeting exon 51 and is normally administered intrathecally, Ataluren is administered in oral doses in DMD patients with 6-min walking distance <350 m. Phase 2b/3 clinical studies have been found to be successful for both of these drugs.[18]

Clinical trials have been completed with shortened versions of DMD gene producing microdystrophin which includes all the essential domains of the protein. These micro-dystrophins are partially functional and administering these genes as gene therapy have shown clinical improvement in animal models. Administering a gene for micro-dystrophin using a recombinant AAV, or rAAV, as the vector to Golden Retriever dogs that naturally develop muscular dystrophy showed promising results in a study published in July 2017. Muscular dystrophy symptoms were reduced for more than 2 years following the treatment and the dogs' muscle strength improved.[19]

A Phase 1/2 clinical trial (NCT03375164) funded by the Biopharmaceutical Company Sarepta Therapeutics at Nationwide Children's Hospital in Columbus, Ohio, is planning to recruit 12 patients in two age groups: 3 months to 3 years and 4–7 years for single dose of the gene therapy encoding for micro-dystrophin. The first patient in the trial has already received the treatment.[20]

Sarepta has started another Phase 1/2a clinical trial (NCT03333590) in November 2017 at Nationwide Children's Hospital (rAAVrh74.MCK.GALGT2). It acts by increasing the expression of a gene called GALGT2 for DMD without targeting the DMD gene. Overproduction of GALG2 gene is thought to produce changes in muscle cell proteins that strengthen them and protect them from damage, even in the absence of functional dystrophin.[21]

  Spinal Muscular Atrophy Top

Zolgensma (brand name of AVXS-101), a gene therapy for infants with SMA type 1 from Novartis, became the most expensive drug ever approved by the Food and Drug Administration (FDA) with a cost of around 2.1 million USD. The pivotal Phase 1 study conducted on SMA Type 1 with AVXS-101 with favorable results formed the primary basis for these submissions. The initial label is for the intravenous (IV) use of AVXS-101 for infants with SMA Type 1, as IV dosing has only been studied in clinical trials in infants.[22] The efficacy and safety data from larger clinical studies will soon become available. The clinical study of AVXS-101 in SMA Type 2 (STRONG) is ongoing, and data from that study will help the study group to determine the final study design for the planned study in children up to 18 years of age (REACH).[23]

Spinraza (brand name for Nusinersen), an ASO which alters the reading frame of SMN2 gene to produce functional SMN protein, was approved by the FDA in December 2016 for SMA I and II. It is administered using intrathecal injection. In two landmark clinical trials, the drug halted the disease progression in around 60% of infants affected by type 1 SMA and also significantly improved motor function, measured by Hammersmith Infant Neurological Examination (HINE) and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores. Adverse effects include increased risk of upper and lower respiratory infections and congestion, ear infections, constipation, pulmonary aspiration, teething, scoliosis, headache, backache, thrombocytopenia, renal damage, and communicating hydrocephalus.[24]



Gene therapy has been somewhat successful in X-linked ALD, late infantile metachromatic leukodystrophy, and Krabbe's disease. In X-linked ALD, mutations in ABCD1 lead to loss of function of the ALD protein.[25] It ultimately results in the demyelination of cerebral white matter, spasticity and neurodegeneration, and finally death. The disease progression can be halted only with allogeneic hematopoietic stem-cell transplantation (HSCT) when Loe's Severity Score is <10. A single-group, open-label, Phase 2–3 safety and efficacy study in 2017 showed the efficacy of hematopoietic stem cell-gene therapy in 17 boys with cerebral ALD in early stages.[26] The investigational therapy involved infusion of autologous CD34 + cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. At the time of the interim analysis with a median follow-up of 29.4 months, all the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth.[27] Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms.[28]

Globoid cell leukodystrophy (GLD), or Krabbe's disease due to deficiency of a lysosomal enzyme, galactosylceramidase, results in widespread CNS and peripheral nervous system demyelination and death in affected infants, typically by 2 years of age. HSCT prior to symptom onset is the only cure currently. The first successful AAV gene therapy experiments in a naturally occurring canine model of GLD that closely recapitulates the clinical disease progression, neuropathological alterations, and biochemical abnormalities observed in human patients were published in 2018.[29] Adapted from studies in twitcher mice, GLD dogs were treated by combination IV and intracerebroventricular injections of AAVrh10 to target both the peripheral and CNS. It resulted in delayed onset of clinical signs, extended life span, correction of biochemical defects, and attenuation of neuropathology.[29]

A Phase I/II clinical trial of gene transfer for treating metachromatic leukodystrophy (MLD) using a safety- and efficiency-improved self-inactivating lentiviral vector TYF-ARSA to functionally correct the genetic defect is recruiting ten participants. MLD patients are normally rescued by HSCT from a matched healthy donor.[30] However, HSCT must be performed at a very early stage of the disease, thus restricting its therapeutic opportunities in MLD patients. This trial uses intracerebral injection to deliver the lentiviral vector carrying a normal ARSA. The primary objectives are to evaluate the safety of the improved self-inactivating lentiviral vector TYF-ARSA, the in vivo gene transfer clinical protocol and the efficacy of degradative metabolite in patients at the time of treatment, assessment of vector integration sites, and finally the long-term correction of the related pathological symptoms.[30]

  Lysosomal Storage Disease Top

Gene therapy using AAV9 vector expressing the Gba gene delivered systemically in Gaucher disease mouse models has been found effective in 2018. The AAV9-CMV-Gba vector, with the expression of Gba driven by the universal cytomegalo virus (CMV) promoter, restored glucocerebrosidase activity in multiple organs and prolonged the life span in tamoxifen-induced GD mice after IV injection.[31] For Sanfillippo disease type B, in four participants, intracerebral rAVV2/5 gene therapy was found to be well tolerated and induced sustained enzyme production in the brain in 2017. The initial specific anti-NAGLU immune response produced in participants later subsided, suggesting acquired immunological tolerance. The best result was obtained in the youngest patient, implying a potential window of opportunity. Promising results were also obtained for mucopolysaccharidosis type I, alpha mannosidosis, Pompe disease, and Fabry disease.[29]

  Gray Matter Degenerative Brain Disease Top

Sands et. al. first successfully tried in infantile mouse model NCL (INCL). An Intracranial injections of AAV2, which expresses human recombinant gene was given. PPT1 activity increased to 15% of the normal levels. Reduction in autofluorescent storage was reported in the results. In another study, intravitreal injection of AAV2–PPT1 was given to infantile mouse NCL (INCL) which resulted into restoration of retinal function after this gene therapy.[32] PPT1 activity was also detected in the brain of intravitreally injected INCL due to anterograde axonal transport. AAV2/9 can cross the neonatal and adult blood–brain barrier and transduce CNS cells; hence, it is preferred. AAVrh. 10–CLN2 has been approved for use in a Phase I clinical trial, which has recently begun recruiting patients. In addition, plan is being done for prenatal transfer of the INCL gene in antenatally detected cases.[33]

An open-label, single-dose, dose-escalation Phase I/II clinical trial AAV9-CLN3 via intrathecal injection of NCL type 3 (CLN 3) has started recruiting two cohorts in 2018 after successful result in animal studies. Initially, in this study, seven participants will be administered a one-time, low-dose intrathecal injection of AAV-CLN3 and subsequently, a second cohort will be administered a one-time, high-dose intrathecal injection of AAV-CLN3 vector construct containing human CLN3 transgene. Both subject cohorts will participate in the ongoing study for a period of at least 3 years. Progranulin gene therapy was also found successful in CLN11 mice.[34]

For monogenetic neurobehavioral disorders such as Rett syndrome, Angelmann syndrome, and Fragile X syndrome, preclinical studies involving animals showed somewhat promising results. However, gene therapy for these diseases has more logistic difficulties as compared to leukodystrophies and other monogenic diseases. Phase I clinical trial for familial amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation utilizing ASOs has also shown promising results.[14]

  Conclusion Top

Apart from DMD and SMA, no recent FDA-approved gene therapy drugs are available apart from research settings till date. With the results of the ongoing trials, future perspective of gene therapy is going to change, especially for leukodystrophies such as ALD and MLD as well as lysosomal storage disease, in which even partial availability of protein can have significant clinical benefits. Many new adenoviral and lentiviral vectors are recently planned to be tried in various neurodegenerative disorders, neurodevelopmental disorders, as well as neuromuscular disorders such as limb girdle muscular dystrophy. In the next decade, for many leukodystrophies and lysosomal storage diseases, patients are likely to have a light of hope due to successful gene therapy options.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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