Follistatin-344

Also known as: FS344, Full-length follistatin

Evidence: Preclinical

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Overview

The 344-residue follistatin precursor, which yields mature circulating follistatin (FS315) after its signal peptide is cut; the human evidence is AAV1-FS344 gene therapy delivering the gene, not an injected protein.

FS344 is one of two follistatin precursors produced by alternative splicing of the FST gene (344 and 317 residues); removing the 29-residue signal peptide gives mature FS315 and FS288 (Shimasaki 1988). The FS344 transcript is what gene-therapy programmes deliver: AAV1.CMV.FS344 was injected into the quadriceps of six Becker muscular dystrophy patients at 3 or 6 x 10^11 vg/kg per leg, where four of six improved 6-minute walk distance by 29 to 125 m with no adverse events (Mendell 2015; Al-Zaidy 2015), and the same vector in six sporadic inclusion body myositis patients gave a reported +56.0 m/year against -25.8 m/year in matched untreated subjects (Mendell 2017). That result was publicly disputed on grounds of control selection and open-label design (Greenberg 2017). Nothing has been injected as follistatin protein in a human study.

Benefits

Improved 6-minute walk distance after AAV1-FS344 gene therapy in small open-label trials (Becker muscular dystrophy n=6, sporadic inclusion body myositis n=6, both contested); muscle mass and strength after AAV follistatin in mice. No injected-protein data.

Dosing reference

Research dose: No dosing data for follistatin protein in any species; research-community range 100 to 300 mcg daily in 10 to 30 day cycles. The human trials dosed an AAV vector (3 to 6 x 10^11 vg/kg per leg), not a peptide
Range: 100 to 300 mcg, 1x daily for 10-30 days
Reconstitution: 1 mL bacteriostatic water
Common vial sizes: 1 mg

No human dosing data for injected follistatin protein; community protocols use short cycles. FS344 is the precursor of circulating FS315, not a tissue-retained variant. Follistatin binds activin A more tightly than myostatin, so activin-pathway effects including FSH suppression come with it (Schneyer 2008). Research-grade material is frequently mislabeled or biologically inactive.

Mechanism

FS344 is a precursor: its 29-residue signal peptide is removed to give mature 315-residue follistatin, the circulating form with low heparan-sulfate affinity (Shimasaki 1988). The shorter FS288, not FS344, is the heparin-binding form that concentrates on cell surfaces, so the idea that FS344 provides tissue-specific retention is backwards. Mature follistatin binds activin A tightly and myostatin and GDF-11 more weakly, blocking them from activin type II receptors (Schneyer 2008). Gene-therapy programmes chose the FS344 splice form specifically to reduce off-target cell-surface binding (Mendell 2015). Removing the myostatin brake on muscle growth is what produced large muscle gains in follistatin-transgenic mice (Lee and McPherron 2001).

Evidence

Preclinical: animal or in vitro data only

AAV1.CMV.FS344 injected into both quadriceps of six Becker muscular dystrophy patients (3 or 6 x 10^11 vg/kg per leg): four improved 6-minute walk distance by 29 to 125 m, two did not, with reduced endomysial fibrosis on biopsy and no adverse events (Mendell et al., 2015)
Follow-up of the same cohort reported sustained ambulation gains (Al-Zaidy et al., 2015)
The same vector in six sporadic inclusion body myositis patients gave a reported +56.0 m/year on the 6-minute walk against -25.8 m/year in eight matched untreated subjects (Mendell et al., 2017)
That inclusion-body-myositis result was publicly contested over control selection and the open-label design (Greenberg, 2017)
One AAV administration of follistatin increased muscle mass and strength in normal and dystrophic mice for over two years (Haidet et al., 2008)
Human-trial status: two small open-label AAV1-FS344 gene-therapy trials, one disputed. No trial of injected follistatin protein, and no regulatory approval

References

Side effects

No safety data exist for injected follistatin protein. In the AAV1-FS344 gene-therapy trials no adverse effects were reported in six Becker muscular dystrophy patients (Mendell 2015). Follistatin binds activin A much more tightly than myostatin (Schneyer 2008), and blocking this pathway with ACE-031 caused nosebleeds and telangiectasia severe enough to stop a trial in boys with Duchenne muscular dystrophy. Research-grade material is frequently inactive or mislabeled, adding contamination risk.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not measured for injected follistatin protein; the AAV gene-therapy construct produces protein for months to years (mouse, >2 years)
Molecular weight: 38007.2 Da